MXPA06007345A

MXPA06007345A - Wound d/ressing and method for controlling severe, life-threatening bleeding.

Info

Publication number: MXPA06007345A
Application number: MXPA06007345A
Authority: MX
Inventors: Kenton W Gregory; William P Wiesmann; Todd D Campbell; Simon J Mccarthy
Original assignee: Hemcon Inc
Priority date: 2003-12-23
Filing date: 2004-12-23
Publication date: 2007-03-23
Also published as: US8668924B2; JP4854084B2; EP1704225B1; US20040243043A1; KR20070009982A; BRPI0417956A; IL175964A0; US20110034410A1; WO2005062880A8; EP1704225A4; ZA200605131B; US7371403B2; AU2004308397A1; WO2005062880A2; US20080213344A1; NO20062551L; WO2005062880A3; EP1704225A2; CA2548191A1; JP2007526026A

Abstract

This invention is directed to advanced hemorrhage control wound dressings, and methods of using and producing same. The subject wound dressing is constructed from a non-mammalian material for control of severe bleeding. The wound dressing for controlling severe bleeding is formed of a biomaterial comprising chitosan, a hydrophilic polymer, a polyacrylic polymer or a combination thereof. The kind of severe, life-threatening bleeding contemplated by this invention is typically of the type not capable of being stanched when a conventional gauze wound dressing is applied with conventional pressure to the subject wound. The wound dressing being capable of substantially stanching the flow of the severe life-threatening bleeding from the wound by adhering to the wound site, to seal the wound, to accelerate blood clot formation at the wound site, to reinforce clot formation at the wound site and prevent bleed out from the wound site, and to substantially prohibit the flow of blood out of the wound site.

Description

APOSITO AND METHOD TO CONTROL PROFESSED BLEEDING, SEVERE FIELD OF THE INVENTION This invention is directed to dressings for hemorrhage control, and to methods for using and producing said dressings. The present dressing is constructed from a material of non-mammalian origin for the control of severe bleeding. The dressing is formed from a bio-material comprising chitosan and / or other hydrophilic polymers to control severe bleeding. The material may alternatively comprise polyacrylic acid or a combination of polyacrylic acid with other polymers. The type of profuse, severe bleeding contemplated by this invention is of the type that can not be stopped when a conventional gauze dressing is applied with conventional pressure to the wound. The dressing can substantially stop the flow of profuse bleeding from a wound adhering to the site of the wound, sealing the wound, accelerating the formation of blood clot at the site of the wound, reinforcing the clot formation at the site of the wound, preventing bleeding from the site of the wound, and substantially preventing the flow of blood away from the site of the wound.

BACKGROUND OF THE INVENTION An advanced bandage for hemorrhage control and methods for its application can substantially increase the available hemostatic methods. To date, the application of continuous pressure with gauze bandages remains the preferred primary intervention technique used to stop blood flow, especially the flow from wounds with profuse bleeding. However, this procedure does not effectively or safely stop the severe flow of blood. This is, and continues to be, an important survival problem in the case of severe profuse bleeding from a wound. Also, it is widely accepted that severe bleeding is the leading cause of death from injuries on the battlefield, which accounts for approximately 50% of such deaths. It is estimated that one third of these deaths can be prevented with improved methods and devices for hemorrhage control. Such improved bleeding control can also prove useful in non-military settings, for example, hospitals and veterinary clinics, in which bleeding is the second leading cause of death after trauma. Currently available hemostatic dressings such as collagen dressings or dried thrombin and fibrin dressings are restricted for use in surgical applications, and are not sufficiently resistant to dissolution in elevated blood flow. They also do not possess sufficient adhesive properties to serve any practical purpose in arresting severe blood flow. These currently available surgical hemostatic dressings are also delicate and therefore prone to failure should they be damaged by folding or when pressure is applied. These are also susceptible to dissolution in hemorrhagic bleeding. Such dissolution and collapse of these bandages can be catastrophic, because this can cause a loss of adhesion to the wound and allow the bleeding to continue without stopping. There is an antecedent technique that refers to chitosan and apitositos de chitosana. For example, the patent E.U.A. No. 4,394,373 issued to Malette et al. uses chitosan in liquid or powder form to bind the blood in amounts of μg / ml. In addition, the patent E.U.A. No. 4,452,785 issued to Malette et al. , is directed to a method to therapeutically obstruct the blood vessels by directly injecting chitosan into the blood vessels. The patent E.U.A. No. 4,532,134 issued to Malette et al. , also refers to hemostasis, inhibition of fibroplasias, and promotion of tissue regeneration by contacting the injured tissue with a solution of chitosan or water-soluble chitosan. Chitosan forms a clot, which prevents bleeding. The patent E.U.A. No. 5,858,350 issued for Vournakis et al. refers to a process for making chitin and chitin derivatives of high purity, biomedical grade obtained from diatomaceous (called protein free although this is not demonstrated by analysis in the patent). The proposed advantage of so-called protein-free chitin / chitosan materials is that they must be significantly less antigenic than current chitin materials obtained from shrimp and crab. My, FL, et al., "Fabrication and Characterization of a Sponge-Like Assymetric Chitosan Membrane as a Wound Dressing," Biomaterials, 22 (2): 165-173 (2001) describe the manufacturing and wound healing function of a Asymmetric chitosan membrane that is produced using a phase inversion method. Chan, MW, et al., "Comparison of Poly-N-acetyl Glucosamine (P-GlcNAc) with Absorbable Collagen (Actifoam), and Fibrin Sealant (Bolheal) for Achieving Hemostasis in a Swine Model of Splenic Hemorrhage", J. Trauma , Injury, Infection, and Critical Care, 48 (3): 454-458 (2000) describe the evaluation of chitosan / chitosan hemostatic patches under moderate blood flow and exudation typical of the porcine spleen capsular denudation test. Colé, DJ, et al., "A Pilot Study Evaluating the Efficacy of a Fully Acetylated Poly-N-Acetyl Glucosamine Membrane Formulation as a Topical Hemostatic Agent", Surgery 126 (3): 510: 517 (1999) describe the evaluation of hemostatic agent in the porcine spleen capsular denudation test. Sandford, Steinnes A., "Biomedical Applications of High Purity Chitosan" in WATER SOLUBLE POLYMERS, SYNTHESIS, SOLUTION PROPERTIES AND APPLICATIONS, ACS Series 467, (WS Shalaby et al., ACS, Washington, DC 1991, Ch 28, 431-445) . This is a general review document that describes the use of chitosan with reference to a chitosan sponge. Mallette, W.G., et al., "Chitosan: A New Hemostat," Annals of Thoracic Surgery 36 (l): 55-58, (1983). See comments concerning previous Malette patents. Olsen, R., et al., In CHITIN AND CHITOSAN, SOURCES, CHEMISTRY, BIOCHEMISTRY, PHYSICAL PROPERTIES AND APPLICATIONS, Elsevier Applied Science, London and New York, 1989, 813-828. This document refers to the agglutination efficiency of chitosan. Japanese patent 60142927 covers a medical league of chitosan with improved adhesiveness. Japanese patent 63090507A2 discloses a water-insoluble chitosan sponge insoluble in 2% acetic acid for external hemostatic application or for wound protection. The patent E.U.A. No. 5,700,476 discloses non-homogeneous structurally based collagen sponges for dressings and / or for implant applications which is formed by lyophilization techniques employing at least one pharmacological agent and at least one sub-structure. The patent E.U.A. No. 2,610,625 refers to sponge structures subjected to freeze drying which are highly effective in arresting the flow of blood or other fluids and which can be absorbed into the body after a time. This patent describes the preparation of a collagen-based sponge. The patent E.U.A. No. 5,836,970 comprises a dressing formed from a combination or mixture of chitosan and alginate. Therefore, there is a need for improved hemostatic dressings that can stop severe hemorrhages and that do not fail after they are bent or loaded with pressure.

SUMMARY OF THE INVENTION The invention is directed to a dressing for first aid / primary intervention for the control of profuse, severe bleeding. Currently there are no low cost appositories that are appropriate for the control of profuse, severe bleeding. There is a need for this type of apposition, especially in the battlefield, where typically 50% of deaths are associated with an inability to immediately control severe bleeding. The dressing of the invention can substantially arrest the flow of profuse hemorrhage from a wound by adhesion to the wound site, sealing the wound, accelerating the formation of blood clot at the site of the wound, reinforcing the formation of clot at the site of the wound, preventing bleeding outside the wound site, and substantially preventing blood flow out of the site of the wound. In one embodiment, a compressed sponge for hemorrhage control comprising a hydrophilic polymer is provided, in which the compressed sponge has a compressed sponge density of about 0.6 to 0.15 g / cm3. The hydrophilic polymer can be an alginate, chitosan, a hydrophilic polyamine, a chitosan derivative, polylysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulosic polymer, a dextran, hyaluronan or combinations thereof. The starch may be amylase, amylopectin, and a combination of amylopectin and amylase. Preferably, the hydrophilic polymer is chitosan. Preferably, the chitosan has a weight average molecular weight of at least about 100 kDa. More preferably, chitosan has a weight average molecular weight of at least about 150 kDa. More preferred, chitosan has a weight average molecular weight of at least about 300 kDa. Preferably, the chitosan has a viscosity at 25 ° C in a 1% solution of acetic acid (AA) with spindle LV1 at 30 rpm which is from about 100 centipoise to about 2000 centipoise. More preferred, chitosan has a viscosity at 25 ° C in a 1% solution of acetic acid (AA) with spindle LV1 at 30 rpm which is from about 125 centipoise to about 1000 centipoise. More preferred still, chitosan has a viscosity at 25 ° C in a 1% solution of acetic acid (AA) with spindle LV1 at 30 rpm which is from about 150 centipoise to about 500 centipoise. The compressed sponge may also comprise an active ingredient. The active ingredient may include, but is not limited to, calcium, thrombin, factor Vlla, factor XIII, thromboxane A2, prostaglandin-2a, epidermal growth factor, platelet-derived growth factor, von Willebrand factor, necrosis factor tumor (TNF), TNF-alpha, transforming growth factor (TGF), TGF-alpha, TGF-beta, insulin-like growth factor, fibroblast growth factor, keratinocyte growth factor, nerve growth factor, penicillin , ampicillin, methicillin, amoxicillin, clavamox, clavulanic acid, amoxicillin, aztreonam, imipenem, streptomycin, kanamycin, tobramycin, gentamicin, vancomycin, clindamycin, erythromycin, polymyxin, bacitracin, amphotericin, nystatin, rifampicin, tetracycline, doxycycline, chloramphenicol, and combinations of the same. In another embodiment, a compressed mixed material sponge for hemorrhage control is provided comprising a hydrophilic polymer sponge and a wettable polymer matrix or wettable polymer matrices within the sponge and / or on the surface of the sponge. The hydrophilic polymer may include alginate, a hydrophilic polyamine, a chitosan derivative, polylysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulosic material, a dextran, hyaluronan or combinations thereof. . The starch can be amylase, amylopectin and a combination of both amylopectin and amylase. The wettable polymer can include non-woven mats, woven mats, molded polymer mesh and low density sponges. The wettable polymer may include, but is not limited to, a chitin, an alginate, a neutralized chitosan, a re-acetylated chitosan, a poly (glycolic acid), a poly (lactic acid), a poly (e-caprolactone), a poly (β-hydroxybutyric acid), a poly (β-hydroxyvaleric acid), a polydioxanone, a poly (ethylene) oxide, a poly (malic) acid, a poly (tartronic acid), a polyphosphazene, a polyethylene, a polypropylene, a metallocene polymer, a polyurethane, a polyvinyl chloride polymer, a polyester, a polyamide and combinations thereof. Preferably, the hydrophilic polymer is chitosan. Preferably, the chitosan has a weight average molecular weight of at least about 100 kDa. More preferably, chitosan has a weight average molecular weight of at least about 150 kDa. More preferred, chitosan has a weight average molecular weight of at least about 300 kDa. Preferably, the chitosan has a viscosity at 25 ° C in a 1% solution of acetic acid (AA) with spindle LV1 at 30 rpm which is from about 100 centipoise to about 2000 centipoise. More preferred, chitosan has a viscosity at 25 ° C in a 1% solution of acetic acid (A?) With spindle LVI at 30 rpm which is from about 125 centipoise to about 1000 centipoise. More preferred still, chitosan has a viscosity at 25 ° C in a 1% solution of acetic acid (AA) which is from about 150 centipoise to about 500 centipoise. The sponge may comprise a textile fiber impregnated with a hydrophilic polymer. The textile fiber is impregnated with a hydrophilic polymer. Preferably, the hydrophilic polymer is chitosan. The hydrophilic polymer may also include, but is not limited to, an alginate, a hydrophilic polyamine, a chitosan derivative, poly-lysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a cellulosic polymer modified, a dextran, hyaluronan or combinations thereof. The starch may include amylase, amylopectin and a combination of both amylopectin and amylase. The wettable mesh can be a non-woven mesh. Preferably, the sponge contains pores with pore diameters of about 15 microns to about 300 microns. More preferred, the sponge contains pores with pore diameters of about 30 microns to about 250 microns. More preferred, the sponge contains pores with pore diameters of about 100 microns to about 225 microns. More preferred, the sponge contains pores with pore diameters of about 125 microns to about 200 microns. More preferably, the sponge contains pores with pore diameters of about 150 microns to about 175 microns. Preferably, the sponge has a surface area available for contact with blood per sponge base surface of approximately 100 cm2 per cm2 to approximately 1000 cm2 per cm2. More preferred, the compressed mixed material sponge has a surface area available for contact with blood per sponge base surface of approximately 200 cm2 per cm2 to approximately 800 cm2 per cm2. More preferably, the sponge has a surface area available for contact with blood per sponge base surface of about 300 cm2 per cm2 to about 500 cm2 per cm2. Preferably, the available mass of bio-material from chitosan per area of the wound surface is from about 0.02 g / cm2 to about 1.0 g / cm2. More preferred, the available mass of chitosan bio-material per wound surface area is about 0.04 g / cm2 to about 0.5 g / cm2. More preferably, the available mass of chitosan bio-material per wound surface area is about 0.06 g / cm2 to about 0.1 g / cm2. The compressed mixed material sponge may also comprise a backing support layer. The backup support layer may be a layer of polymeric material. The polymeric material may be a non-biodegradable synthetic material or a biodegradable polymer normally present in Nature. Synthetic biodegradable materials may include poly (glycolic acid), poly (lactic acid), poly (e-caprolactone), poly (β-hydroxybutyric acid), poly (β-hydroxyvaleric acid), polydioxanone, poly (ethylene oxide), poly (malic) acid, poly (tartronic acid) , polyphosphazene, polyethylene copolymers, polypropylene copolymers, the copolymers of the monomers used to synthesize said polymers or combinations thereof. The polymers normally present in Nature may include chitin, algin, a starch, dextran, collagen, albumin and a combination thereof. Synthetic polymers can include polyethylene, polypropylene, a metallocene polymer, a polyurethane, a polyvinyl chloride polymer, a polyester, a polyamide or combinations thereof. Preferably, the compressed mixed material sponge has a degree of adhesion to the wound site of about 40 kPa to about 500 kPa. More preferred, the compressed mixed material sponge has a degree of adhesion to the wound site of about 60 kPa to about 250 kPa. More preferably, the compressed mixed material sponge has a degree of adhesion to the wound site of about 100 kPa to about 200 kPa. The compressed mixed material sponge can form an adhesive material in combination with the blood flowing from said wound at a blood-dressing interface. Preferably, the adhesive material is a chitosan-based adhesive material. Preferably, the adhesive material based on chitosan has a pH of no more than about 6.3 when the wound is sealed. More preferred, the chitosan-based adhesive material preferably has a pH of no more than about 4.5 when the wound is sealed. Most preferably, the adhesive material based on chitosan has a pH of no more than about 4.0 when the wound is sealed. The adhesive material may comprise an acid which is selected from the group consisting of acetic acid, formic acid, lactic acid, ascorbic acid, hydrochloric acid and citric acid. Preferably, the compressed mixed material sponge has a thickness that is not less than about 3.0 mm and not more than about 8 mm. More preferred, the compressed mixed material sponge has a thickness that is not less than about 3.5 mm and not more than about 7 mm. More preferably, the compressed mixed material sponge has a thickness which is not less than about 4.0 mm and not more than about 6 mm. Preferably, the compressed mixed material sponge has a final tensile stress of about 0.1 MPa to about 10 MPa. More preferred, the compressed mixed material sponge has a final tensile stress of about 0.15 MPa to about 0.8 MPa. More preferably, the compressed mixed material sponge has a final tensile stress of about 0.25 MPa to about 0.5 MPa. Preferably, the compressed mixed material sponge has a final stretch of about 5%. More preferred, the compressed mixed material sponge has a final stretch of about 10%. More preferably, the compressed mixed material sponge has a final stretch of about. In another embodiment, a method is provided for preparing a compressed sponge for bleeding control comprising (a) preparing by freeze / lyophilization a low density sponge; and (b) compressing the low density sponge at a preferred rate of about 10 mm per minute and at a preferred controlled temperature of 80 ° C whereby a compressed sponge with a density of about 0.1 to about 0.2 g / cm 3 is obtained. In another embodiment, a method is provided for preparing a compressed sponge for hemorrhage control comprising (a) preparing a low density sponge using methods other than freeze / lyophilization preparation of a low density sponge; and (b) compressing the subsequent low density sponge at a rate of about 10 mm per minute and at a preferred controlled temperature of about 80 ° C whereby a compressed sponge with a density of about 0.1 to about 0.2 g / cm 3 is obtained. . Preferably, the low density sponge has a density of about 0.01 g / cm3 to about 0.035 g / cm3. Preferably, the compressed sponge has a density of about 0.1 g / cm3 to about 0.15 g / cm3.

In another embodiment, a method is provided for preparing a compressed mixed material sponge for hemorrhage control comprising a) de-gasifying the bio-material solution from chitosan by heating the bio-material chitosan solution and applying a vacuum to the same; b) freezing the bio-material solution of chitosan; c) removing the water from the interior of the frozen chitosan bio-material without damaging the structural integrity of the frozen chitosan bio-material in such a way that the water in the chitosan bio-material passes from a solid phase to a gaseous phase; d) compressing the bio-material of chitosan at a preferred rate of about 10 mm per minute thereby obtaining a compressed sponge with a density of about 0.1 to about 0.2 g / cm 3; and e) baking the compressed chitosan sponge at 80 ° C for 30 minutes. Preferably, the temperature is gradually reduced over a predetermined time interval during freezing of the chitosan bio-material from step (b). Preferably, the temperature of step (b) is a final freezing temperature of not more than about -25 ° C. More preferred, the step procedure (b) implies a final freezing temperature of no more than about -35 ° C. More preferably, the temperature of step (b) is a final freezing temperature of no more than about -45 ° C. Water removal can be effected by lyophilization of the frozen chitosan bio-material. The process may also comprise a step of adding argon, nitrogen and helium back to the de-gassed chitosan solution prior to freezing. The compressed sponge can be sterilized. Preferably, the compressed sponge is sterilized by gamma irradiation. In another embodiment, a method for preventing severe bleeding is provided in an individual comprising administering a compressed sponge or a sponge of compressed mixed material. Preferably, the individual is a mammal. More preferred, the mammal is human. Preferably, the individual suffers from severe bleeding in a manner that results in the loss of approximately 30-40% of the total blood volume within 20 to 30 minutes if the bleeding is left uncontrolled. Preferably, the compressed sponge or sponge of compressed mixed material is applied with a pressure of approximately 60 to 80 kPa directly on the bleeding lesion and held in place for 3 to 5 minutes before releasing, packing and bandaging. In another embodiment, a bandage box for treating severe bleeding comprising a compressed sponge or a compressed sponge of mixed material, gauze rolls for packaging and an Ace bandage for bandaging a wound is provided. In another embodiment, a method is provided for the coupling and mechanical meshing of compressed or compressed sponges of mixed material comprising pressing the sides of the sponge that come into contact with the tissue against a macro-textured surface. The macro-textured surface may include surfaces prepared by chemical etching, surfaces prepared by surface ablation by ion beam, surfaces prepared by mechanical cutting, and surfaces prepared by laser ablation. In another embodiment, a method is provided for improving the mechanical traction of compressed sponges or compressed mixed material comprising pressing the sides of the sponge that come into contact with the tissue against a macro-textured surface. Preferably, the macro-textured surface is selected from the group consisting of surfaces prepared by chemical etching, and surfaces prepared by particle blasting techniques. In another embodiment, a method is provided for limiting or stopping the formation of thick crust on the surface of the sponges of mixed material or of compressed mixed material comprising covering the surface of the sponge with a polymeric film, a polymer plate, a raised plastic plate or a breathable membrane film, impervious to moisture. In another embodiment, a low density sponge, in which the sponge is formed by compressing a sponge with an initial density of approximately less than 0.05 g / cm 3 until the sponge reaches a density of approximately less than 0.08 g / cm 3. The sponge can be formed by a process other than freezing or lyophilization. Preferably, the sponge is formed using a method that is selected from the group consisting of a phase inversion process, sponges that are prepared by covalent attachment of active components to preformed matrices, and foaming techniques. In another embodiment, the compressed sponge and the compressed mixed material sponge may also comprise at least one additional hydrophilic polymer. The additional hydrophilic polymer may include, but is not limited to, alginate, chitosan, a hydrophilic polyamine, a chitosan derivative, poly-lysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulosic polymer, a dextran, hyaluronan or combinations thereof. The starch may include, but is not limited to, amylase, amylopectin and a combination of amylopectin and amylase. Preferably, the hydrophilic polymer is chitosan. In another embodiment a compressed sponge for hemorrhage control comprising a hydrophilic polymer is provided, in which the compressed sponge has a compressed sponge density of about 0.6 to 0.15 g / cm3 the hydrophobic polymer can be a polyacrylic acid. Preferably, the compressed sponge may also comprise an active ingredient. The active ingredient may include, but is not limited to, calcium, thrombin, factor Vlla, factor XIII, thromboxane A2, prostaglandin-2a, epidermal growth factor, platelet-derived growth factor, von Willebrand factor, necrosis factor tumor (TNF), TNF-alpha, transforming growth factor (TGF), TGF-alpha, TGF-beta, insulin-like growth factor, fibroblast growth factor, keratinocyte growth factor, nerve growth factor, penicillin , ampicillin, -meticilin, amoxicillin, clavamox, clavulanic acid, amoxicillin, aztreonam, imipenem, streptomycin, kanamycin, tobramycin, gentamicin, vancomycin, clindamycin, erythromycin, polymyxin, bacitracin, amphotericin, nystatin, rifampicin, tetracycline, doxycycline, chloramphenicol, or combinations thereof. In another embodiment, a sponge of compressed mixed material for hemorrhage control is provided comprising a hydrophilic polymer sponge and a wettable polymer matrix or wettable polymer matrices within the sponge and / or on the surface of the sponge; wherein the hydrophobic polymer is polyacrylic acid. Wettable polymeric matrices may include non-woven mats, woven mats, molded polymer mesh and low density sponges. The wettable polymer matrix can include a chitin, an alginate, a neutralized chitosan, a re-acetylated chitosan, a poly (glycolic acid), a poly (lactic acid), a poly (e-caprolactone), a poly (ß) acid -hydroxybutyric acid), a poly (β-hydroxyvaleric acid), a polydioxanone, a poly (ethylene oxide), a poly (malic) acid, a poly (tartronic acid), a polyphosphazene, a polyethylene, a polypropylene, a polymer of metallocene, a polyurethane, a polyvinyl chloride polymer, a polyester, a polyamide or combinations thereof. The sponge may comprise a textile fiber impregnated with a hydrophilic polymer. Preferably, the textile fiber is impregnated with a hydrophilic polymer, in which the hydrophobic polymer is polyacrylic acid. Preferably, the wettable polymer matrix is a non-woven mesh. Preferably, the sponge contains pores with pore diameters of about 15 microns to about 300 microns. More preferred, the sponge contains pores with pore diameters of about 30 microns to about 250 microns. More preferred, the sponge contains pores with pore diameters of about 100 microns to about 225 microns. More preferred, the sponge contains pores with pore diameters of about 125 microns to about 200 microns. More preferably, the sponge contains pores with pore diameters of about 150 microns to about 175 microns. Preferably, the sponge has a surface area available for contact with blood per base surface of the sponge of 100 cm2 per cm2 up to 1000 cm2 for each cm2 approximately. More preferably, the sponge has a surface area available for contact with blood per base surface of the sponge of 200 cm2 per cm2 to 800 cm2 for each cm2 approximately. More preferably, the sponge has a surface area available for contact with blood per sponge base surface of about 300 cm2 per cm2 to about 500 cm2 per cm2. The compressed mixed material sponge may also comprise a backing support layer. Preferably, the backup support layer may be a layer of polymeric material. Preferably, the polymeric material is a non-biodegradable synthetic material or a biodegradable polymer normally present in Nature. Synthetic biodegradable materials may include, but are not limited to, poly (glycolic) acid, poly (lactic acid), poly (e-caprolactone), poly (β-hydroxybutyric acid), poly (β-hydroxyvaleric acid), polydioxanone, poly (ethylene oxide), poly (malic) acid, poly (tartronic acid), polyphosphazene, polyethylene copolymers, polypropylene copolymers, the copolymers of the monomers used to synthesize said polymers or combinations thereof. Polymers normally present in Nature may include, but are not limited to, chitin, algin, a starch, dextran, collagen, albumen, or combinations thereof. Synthetic polymers may include, but are not limited to, polyethylene, polypropylene, a metallocene polymer, a polyurethane, a polyvinyl chloride polymer, a polyester, a polyamide or combinations thereof. Preferably, the compressed mixed material sponge has a degree of adhesion to the wound site of about 40 kPa to about 500 kPa. More preferred, the compressed mixed material sponge has a degree of adhesion to the wound site of about 60 kPa to about 250 kPa. More preferably, the compressed mixed material sponge has a degree of adhesion to the wound site of about 100 kPa to about 200 kPa. The sponge of compressed mixed material can form an adhesive material in combination with the blood flowing from said wound in a blood-tight interface. Preferably, the adhesive material preferably has a pH of not less than about 5.5 when the wound is sealed. More preferred, the adhesive material preferably has a pH of no more than about 6.5 when the wound is sealed. Most preferably, the adhesive material preferably has a pH of no more than about 7.5 when the wound is sealed. Preferably, the adhesive material comprises an acid which is selected from the group consisting of acetic acid, formic acid, lactic acid, ascorbic acid, hydrochloric acid, and citric acid. Preferably, the compressed mixed material sponge has a thickness that is not less than about 3.0 mm and not more than about 8 mm. More preferred, the compressed mixed material sponge has a thickness that is not less than about 3.5 mm and not more than about 7 mm. More preferably, the compressed mixed material sponge has a thickness which is not less than about 4.0 mm and not more than about 6 mm. Preferably, the compressed mixed material sponge has a final tensile stress of about 0.1 MPa to about 10 MPa. More preferred, the compressed mixed material sponge has a final tensile stress of about 0.15 MPa to about 0.8 MPa. More preferably, the compressed mixed material sponge has a final tensile stress of about 0.25 MPa to about 0.5 MPa. Preferably, the compressed mixed material sponge has a final stretch of about 5%. More preferred, the compressed mixed material sponge has a final stretch of about 10%. Most preferably, the compressed mixed material sponge has a final stretch of about 15%. In another embodiment, there is provided a method for preparing a compressed sponge according to claim 1 for hemorrhage control comprising the steps of (a) preparing by freeze / lyophilization a low density sponge; and (b) compressing the low density sponge at a preferred rate of 10 mm per minute and at a preferred controlled temperature of 80 ° C whereby a compressed sponge with a density of about 0.1 to about 0.2 g / cm 3 is obtained. In another embodiment, a method is provided for preparing a compressed sponge for hemorrhage control comprising the steps of (a) preparing a low density sponge using methods other than the freeze / lyophilization preparation of a low density sponge; and (b) compressing the subsequent low density sponge at a rate of 10 mm per minute and at a preferred controlled temperature of 80 ° C whereby a compressed sponge with a density of about 0.1 to about 0.2 g / cm 3 is obtained. Preferably, the low density sponge has a density of about 0.01 g / cm3 to about 0.035 g / cm3. Preferably, the compressed sponge has a density of about 0.1 g / cm3 to about 0.15 g / cm3. In another embodiment, a method is provided for preparing a compressed mixed material sponge for hemorrhage control comprising a) de-gasifying the bio-material solution by heating the bio-material solution and applying a vacuum thereto; b) freeze the bio-material solution; c) removing the water from the interior of the frozen bio-material without damaging the structural integrity of the frozen bio-material in such a way that the water in the bio-material passes from a solid phase to a gaseous phase; d) compressing the bio-material at a preferred rate of about 10 mm per minute thereby obtaining a compressed sponge with a density of about 0.1 to about 0.2 g / cm3; and e) baking a compressed sponge at 80 ° C for 30 minutes. Preferably, the temperature is gradually reduced over a predetermined time interval during freezing of the biomaterial of step (b). Preferably, the temperature of step (b) is a final freezing temperature of no more than about -5 ° C. More preferred, the temperature of step (b) is a final freezing temperature of not more than about -35 ° C. More preferably, the temperature of step (b) is a final freezing temperature of not more than about -25 ° C. Preferably, the removal of water is done by lyophilizing the frozen bio-material. The process may also comprise a step of adding argon, nitrogen and helium back to the de-gassed chitosan solution prior to freezing. The sponge can be sterilized compressed sponge. Preferably, the compressed sponge is sterilized by gamma irradiation. In another embodiment, a method for preventing severe bleeding is provided in an individual comprising administering a compressed sponge or a sponge of compressed mixed material. Preferably, the individual is a mammal. More preferred, the mammal is human. Preferably, the individual suffers from severe bleeding in a manner that results in the loss of approximately 30-40% of the total blood volume within 20 to 30 minutes if the bleeding is left uncontrolled. Preferably, the compressed sponge or sponge of compressed mixed material is applied with a pressure of approximately 60 to 80 kPa directly on the bleeding lesion and held in place for 3 to 5 minutes before releasing, packing and bandaging the wound. In another embodiment, a method is provided for preventing severe bleeding in an individual comprising administering a compressed sponge or a sponge of compressed mixed material. Preferably, the individual is a mammal. More preferred, the mammal is human. Preferably, the individual suffers from severe bleeding in a manner that results in the loss of approximately 30-40% of the total blood volume within 20 to 30 minutes if the bleeding is left uncontrolled. PreferablyThe compressed sponge or sponge of compressed mixed material is applied with a pressure of approximately 60 to 80 kPa directly on the bleeding lesion and held in place for 3 to 5 minutes before releasing, packing and bandaging the wound. In another embodiment, a bandage box for treating severe bleeding comprising a compressed sponge or a compressed sponge of mixed material, gauze rolls for packaging and an Ace bandage for bandaging a wound is provided. In another embodiment, a method is provided for the coupling and mechanical mesh formation of compressed or compressed sponges of mixed material comprising pressing the sides of the sponge that come into contact with the tissue against a macro-textured surface. The macro-textured surface may include surfaces prepared by chemical etching, surfaces prepared by surface ablation by ion beam, surfaces prepared by mechanical cutting, and surfaces prepared by laser ablation. In another embodiment, a method is provided for improving the mechanical traction of compressed sponges or compressed mixed material comprising pressing the sides of the sponge that come into contact with the tissue against a macro-textured surface. Preferably, the macro-textured surface is selected from the group consisting of surfaces prepared by chemical etching, and surfaces prepared by particle blasting techniques. In another embodiment, a method is provided for limiting or stopping the formation of thick crust on the surface of the sponges of mixed material or compressed mixed material comprising covering the surface of the sponge with a polymeric film, a polymer plate, a high plastic plate or a breathable membrane film, impervious to moisture. In another embodiment, a low density sponge is provided, in which the sponge is formed by compressing a sponge with a density of approximately less than 0.05 g / cm 3 until it reaches a density of approximately less than 0.08 g / cm 3, and in which the sponge is formed by a procedure other than freezing or lyophilization. Preferably, the sponge is formed using a method that is selected from the group consisting of a phase inversion process, sponges which are prepared by covalent attachment of active components to preformed matrices and foaming techniques. In another embodiment, a compressed sponge and a compressed mixed material sponge are provided, in which the sponges also comprise a hydrophilic polymer in combination with the polyacrylic acid. The hydrophilic polymer may include, but is not limited to, alginate, chitosan, a hydrophilic polyamine, a chitosan derivative, poly-lysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulosic polymer, a dextran, hyaluronan or combinations thereof. The starch may include amylase, amylopectin and a combination of amylopectin and amylase. Preferably, the hydrophilic polymer is chitosan.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a photo-digital image of a cross section through an initially non-compressed dressing. Figure 2 shows a photo-digital image of cross-section through oriented lamella structures in a non-compressed dressing. Figure 3 shows a photomicrograph of light from the interconnected pores of the appositite structure based on chitosan sectioned from normal to base. Figure 4 shows a photograph of apposition based on bio-material chitosan after heating and compression. Figure 5 shows an electron scanning photomicrograph of a typical base surface of compressed chitosan dressing. Higher increase intercalation (bar = 100 microns). Figure 6 shows a histological section stained through the site of spleen / chitosan injury and the adjacent surface of the spleen. Clotted clot response (A) with a fibrin / blood platelet-rich blood clot (B) between patch and spleen. The figures show very good adhesion between the spleen and the chitosan. Figure 7 shows a photograph of a thoracic aorta lesion sealed with a chitosan patch. Figure 8 shows a fixed thoracic aorta demonstrating the perforation lesion. Figure 9 shows a histological section stained through a thoracic aortic lesion. Figure 10 shows a photograph of an in vitro burst pressure failure in a tightly adherent dressing. Figure 11 shows a histogram of water and blood adsorption results for samples irradiated with gamma radiation and non-irradiated samples (ie not sterilized).

Figures 12A to 12C show detailed drawings of the appearance of a typical chitosan sponge. Figures 13A to 13B show the effect of compression on the internal structure of the sponge as seen in sponge with 2% typical sectioned solution compressed from 17 mm to 5 mm thick. Figure 14 shows a detailed drawing of an individual lamella showing the indentations of the surface. Figure 15 shows a detailed drawing of the surface of a foil. Figures 16A to 16G show electronic scanning microscopy (SEM) images of the indented structure projecting towards the upper surface of the foil. These figures show the indentations at several increases. Figure 17 shows a light microscope image with side illumination of a single lamella removed near the base of a chitosan sponge using micro-tweezers. The fine indented structure can be observed projecting in normal to the upper surface of the lamella.

DETAILED DESCRIPTION OF THE INVENTION A. Compressed sponges and compressed mixed material sponges The invention is directed to a first aid / primary intervention dressing for control of profuse, severe bleeding. Such bleeding can be fatal in bullet injuries and severe lacerations of the arteries. There is an urgent need for this type of apposition, especially in the battlefield, where typically 50% of all deaths are associated with an inability to immediately control severe bleeding. An advanced dressing for control of profuse, severe bleeding should preferably have the following properties: i) application quickly and easily in one step after removing it from the package; ii) rapid and intense coagulation of the blood; iii) fast and strong adhesion to the tissue; iv) strong internal cohesive properties; v) fast and strong wound sealing; vi) resistance to dissolution under intense blood flow; vii) good adaptation to the injury; viii) good initial mechanical seating of the bandage on the tissue to stop the sliding by controlled texture of the surface that comes into contact with the tissue; and ix) ability to be treated almost without compromising effectiveness. For this end, the invention is directed to advanced dressings for hemorrhage control, and methods for using and producing said dressings. The type of profuse, severe bleeding contemplated by this invention is typically the type that can not be stopped when a conventional gauze dressing with conventional pressure is applied to the individual's wound. Alternatively, the nature of profuse, severe bleeding is such that it does not stop when a conventional gauze dressing is applied with conventional pressure to the wound, and if it is not controlled by other means, it can result in the person falling. in a state of hypotension. In other words, profuse, severe bleeding generally can not be stopped when a conventional gauze dressing with conventional pressure is applied to the wound and can result in the person's blood systolic pressure falling to levels less than 90 mm. Hg. Profuse, severe bleeding can also be described as a constant high blood flow greater than approximately 90 ml of blood lost per minute, so that approximately 20 minutes of bleeding may result in a loss of more than approximately 40% of blood. total of a human male gender of 70 kg, and the volume of blood lost can substantially reduce the likelihood of a person's survival. If this type of bleeding does not stop within 5-10 minutes, an injured person may fall into a condition of hypotension, such that the blood pressure drops to less than 60 mm Hg. In many cases, severe bleeding is caused by a ballistic projectile injury or a puncture-piercing injury or a traumatic injury with a blunt object. In other cases, severe bleeding is caused by coagulopathy or internal trauma or surgical trauma, motor vehicle trauma, agricultural accidents, and the like. The dressing of the invention can stop such severe bleeding which is caused by a substantial wound of the artery or a substantial wound of the veins having a blood flow velocity of at least about 90 ml / minute, and adhering to the wound site by applying direct pressure to the dressing during a time interval no greater than about five minutes. The dressing also acts quickly to seal the wound, and facilitates substantial coagulation and agglutination of severe bleeding from the wound site, and stops severe bleeding with temporary application of direct pressure to the dressing. The dressing has a high resistance to dissolution in high blood flow, and has adequate internal cohesion properties. This has enough flexibility to adjust to the injury and stiffness to withstand rough handling. The dressing of the present invention is formed from a bio-material to control severe bleeding. Preferably, the bio-material comprises a material of non-mammalian origin. Preferably, the material of non-mammalian origin is poly [ß- (1-4) -2-amino-2-deoxy-D-glucopyranose], more commonly known as chitosan. The dressing is configured with a woven or sponge-like configuration by using steps that produce a structure or intermediate shape. The bio-material comprises an inter-connected open porous structure, and / or oriented open lamella structure, and / or an open tubular structure, and / or an open honeycomb structure, and / or a filamentous structure. The apposition has domains or pores of free space connected to each other with a pore of approximately 15 microns to approximately 300 microns; about 30 microns to about 250 microns; about 100 microns to about 225 microns; about 125 microns to about 200 microns; and more preferably about 150 microns to about 175 microns. The dressing has a surface area available for contact with blood per base surface of said dressing preferably of at least about 100 cm2 per each cm2, more preferred at least about 200 cm2 per each cm2, and most preferably by at least about 300 cm2 per cm2. The available mass of bio-material of chitosan per surface area of the wound is preferably from about 0.02 g / cm2 to about 1.0 g / cm2; more preferred, the available mass of bio-material from chitosan per surface area of the wound is from about 0.04 g / cm2 to about 0.5 g / cm2; and more preferred still, the available mass of chitosan bio-material per wound surface area is about 0.06 g / cm2 to about 0.1 g / cm2. By the phrase "per base surface" it is meant, for example, that if 1 cm x 1 cm is taken from the surface of the base which is generally in contact with the blood, then the blood can be expected to enter into the blood. contact with at least 100 cm2 of chitosan surface area due to the open sponge structure. The sponges can be prepared by methods including, but not limited to, phase inversion procedures, freezing, lyophilization, covalent attachment of active components to preformed matrices, and foaming techniques. Also, the dressing has an average dissolution rate per base area surface of said dressing when adhered to said wound site, at a temperature of about 37 ° C, preferably not more than about 0.008 grams per minute per cm 2, more preferred no greater than about 0.005 grams per minute per cm2, and more preferred still not greater than about 0.002 grams per minute per cm2. The dressing of the present invention preferably has a density of at least about 0.05 g / cm 3, more preferred at least about 0.07 g / cm 3, and most preferably at least about 0.11 g / cm 3. This may have a compression load preferably up to a compression density of at least about 0.05 g / cm 3, more preferred at least about 0.07 g / cm 3, more preferred still at least about 0,095 g / cm 3, and preferably not greater than about 0.2 g / cm3.

The dressing of the invention typically contains chitosan with a number average molecular weight of at least about 50 kDa, preferably at least about 75 kDa, more preferred at least about 100 kDa, and most preferably at least about 150 kDa (molecular weights are determined by gel permeation chromatography relative to reference standards of polyethylene glycol in 0.01 M sodium acetate, pH 5.5). Preferably, the adhesive material based on chitosan has a pH of no more than about 6.3 when the wound is sealed. More preferred, the chitosan-based adhesive material preferably has a pH of no more than about 4.5 when the wound is sealed. Most preferably, the adhesive material based on chitosan has a pH of no more than about 4.0 when the wound is sealed. With respect to dressings in which the hydrophilic polymer is polyacrylic acid, preferably the adhesive material has a pH of not less than about 5.5 when the wound is sealed. More preferred, the adhesive material preferably has a pH of not less than about 6.5 when the wound is sealed. Most preferably, the adhesive material based on chitosan has a pH of not less than about 7.5 when the wound is sealed.

Chitosan also preferably has a weight average molecular weight of at least about 100 kDa, more preferred at least about 150 kDa, and most preferably at least about 300 kDa (molecular weights are determined by permeation chromatography in gel with reference to polyethylene glycol reference standards in 0.01 M sodium acetate, pH 5.5). The chitosan in the dressing also has a Brookfield LV DV-II + viscosity at 25 ° C in a 1% acetic acid (AA) solution with a spindle at about 30 rpm which is preferably from about 100 centipoise to about 2000 centipoise , more preferred about 125 centipoise up to about 1000 centipoise, and even more preferred about 150 centipoise up to 500 centipoise. The spindle is preferably a spindle LV1, LV2, LV3 or LV4. The molecular weights and viscosities referred to above are with respect to apposites of substantially pure chitosan and dressings that are formed with a layer of chitosan adsorbed on the surface. In the case of a dressing containing a covalently bonded surface layer of chitosan, lower viscosities and molecular weights of chitosan are preferred. The dressing of the present invention may comprise cationic salts of chitosan to promote tissue adhesion and tissue sealing. Preferably, the cationic salts of chitosan may include, but are not limited to, chitosan formate, chitosan acetate, chitosan lactate, chitosan chloride, chitosan ascorbate and chitosan citrate. Chitosan has a degree of de-acetylation, which is typically at least about 70%, preferably at least about 75%, more preferred at least about 80%, even more preferred at least about 85%. It is preferable to compact a low density sponge (density <0.03 g / cm3 solid), instead of compacting a medium density sponge (0.1 g / cm3> density> 0.5 g / cm3 in solid volume) or a sponge medium density, which is already at the preferred density, up to its optimum density of around 0.15 g / cm3. This is because the method of forming the low density sponge sponge results in significantly thinner wall thicknesses between the pores of the sponge compared to the wall thicknesses in sponges with medium density and higher densities. In addition, these higher density sponges often have a more connected structure which increases the rigidity of the sponge and reduces the resistance to cracking. Multiple thin walls in low density spongesWhen they are compacted to higher densities, they make sponges more flexible and more resistant than sponges with medium and higher density, which are produced with more structures connected to each other, as well as thicker and therefore more rigid cell walls. The densification of the sponge can be achieved either by unidirectional or bidirectional application of a controlled compaction speed at a fixed temperature. A preferred densification of sponge is achieved by unidirectional compaction at 80 ° C and with a sponge moisture content between 2% and 5% by weight approximately. As an example of uni-axial compaction, it is compacted at a controlled compaction speed of 10.0 cm (x direction), x 10.0 cm (x direction) x 1.70 cm (z direction) at 10 mm / minute in the z direction between flat aluminum plates, horizontally oriented (xy plane) of 63.5 cm x 50.8 cm in a shuttle press Geo Knight 394-TS at 2,812 kg / cm2 (40 psi). The compaction speed is controlled by pressure adjustment and use of a Parker SPF200B needle valve. The final 0.55 cm thickness of the sponge is controlled using at least two spacer bars of 50 cm x 2 cm x 0.55 cm. The initial density of the sponge is 0.033 g / cm3. The density of the sponge after compaction is 0.10 g / cm3. Other spacer controls such as 0.15 cm, 0.35 cm and 0.45 cm height have been used to achieve sponges of 0.375 g / cm3, 0.16 g / cm3 and 0.125 g / cm3 respectively. Bidirectional compaction can be carried out (compression of the plate in the "z" and "x" or "y" directions) to reduce a sponge of 5 cm x 5 cm x 1.7 cm to a sponge of 2.5 cm x 2.5 cm x 0.55 cm. Complex shapes can be compacted using vacuum bagging techniques in which a closed plastic film is wrapped over the surface of the sponge and air is removed from the inside of the sponge and plastic film jacket to a controlled level by application of a vacuum. A hot roller press can also be used to compress the sponge tape and other sponge profiles. It is preferred that said sponge ribbons and profiles are reinforced with a mesh of internal mixed material if they are compacted using a roller press. A preferred embodiment of the compacted continuous sponge filament of mixed material is that in which the filament is stretched through a rod die coated with heated Teflon ™ (80 ° C), with a cap controlled at the entrance of around from 2.5 mm in diameter to 0.67 mm in diameter at full compaction. Humid conditions, heat application and controlled compaction speed are chosen to optimize ductile compaction while minimizing the brittle collapse of the sponge. The brittle collapse of the sponge results in loss of the mechanical integrity of the sponge by cracking. The optimum compaction of the sponge to fine areas connected to each other is achieved more adequately in sponges with spherical pores connected to each other (for example dodecahedron). The pore size of non-compacted sponge is optimum between 30 and 120 microns with polymer wall thicknesses of 1 to 20 microns. In the case of sponges with lamella structure or honeycomb type, it is more appropriate that the structure be oriented uniformly around 30 to 40 degrees from the normal direction of uniaxial compaction. It is possible to obtain said uniform structure during freezing by applying a shear stress in the normal to the direction of the thermal gradient. Said shear stresses are achieved by applying uniform load in the direction of freezing and with application of reduced load in the direction normal to heat loss. Near vertical structures are compacted less easily without brittle fracture or random channel formation. In fact, the vertical structures that originate from the nucleation of ice of upper surface, during freezing in an open mold, lead to a vertical crust layer in the sponge that does not compact easily, which causes rigidity in the sponge and that quickly dissolves when it comes in contact with blood or aqueous solutions. In addition, horizontal structures are undesirable because they are compacted elastically in the mass and with loss of pore interconnectivity in the surfaces. In addition, in the lamella or honeycomb type sponges, it is desired that the wall structure have an indented or ciliated surface. Said surfaces in the lamellae or honeycomb walls are achieved under specific conditions during the phase separation controlled by freezing the ice and the hydrophilic polymer. Usually, the indentations or cilia are orthogonal with respect to the surface of the lamella or honeycomb projecting from the surface as thin walls, "teeth", "honeycombs" or columns of 3 to 10 microns and 3-10 microns in length in the case of indentations or 2-3 microns in diameter in the case of cilia. These are distributed on the lamella or honeycomb wall, often with regular labyrinth type. One wall adjacent to the other at intervals of 5-10 micras but always separated. The degree of the indentations seems to be controlled by the molecular weight of the polymer, its molecular weight distribution, the degree of elongated rod type properties before and during phase separation and the cooling rate. During densification, these indentations act to maintain the pore connections by spreading a desired controlled spacing of the lamellae to at least about 5 to 10 microns as the lamellae are compacted against each other. The cilia and surface indentations also play an important role in the adhesion by helping the mechanical anchoring and coupling of the surfaces. Therefore, the surface texture of the indented / ciliated structures is more adequately conserved during densification. This can be achieved by compaction of the positive sponge surface to a negative base surface. Ideally, the texture of this base surface is the negative release of the indented / ciliated surface. Therefore, with minimum load application, the first surface fits exactly within the second surface providing a maximum surface area contact between the two surfaces. In addition, when removing the first surface from the second, there must necessarily be an adequate release of the surfaces without damage or significant loss of surface. As with this micro-keying of surfaces during compaction, it is also possible to create macro-patterns on the surface of the sponge by applying a patterned surface against which the sponge is compacted during the compaction step. Such patterning can include non-skid patterns that can help with the application of the primary hemostatic bandage to the tissue lesion. It is possible to compact rectangular, cylindrical, spherical, complex shapes and forms of mixed material up to the optimal densities for the control of hemorrhages. Sponges can be prepared with mixed material forms. A typical rectangular mixed material form may include an insoluble, but wettable, non-woven or woven mesh within the sponge. This can typically be done by carrying out the phase separation process for sponge formation with the mesh present within the pre-sponge solution. A non-woven mesh material is preferred because this material is more compatible with the compaction process of the sponge and is less likely to cause tears in the sponge during densification. Another modality is one in which a low density chitosan sponge is formed from a chitosan solution of 0.25% to 1% by freezing / lyophilization to a chitosan sponge. This sponge is then re-acetylated to a chitin sponge form by immersion for at least 24 hours in 99% acetic anhydride at room temperature. This re-acetylated sponge can then be applied on or in a solution for chitosan mold (1% to 2%), in which the chitosan solution is configured as a sponge by freezing / lyophilization. The chitosan sponge of mixed material reinforced by the chitin sponge is subsequently compacted to an optimum density. Another embodiment of the mixed material form is one in which a chitosan sponge is formed, most preferably by a freeze / lyophilization process. This chitosan sponge is then neutralized by washing with a 0.1 M NaOH solution, and then rinsed with water to remove the residual sodium and sodium hydroxide salts. The neutralized chitosan sponge (now insoluble in water and blood) is placed in or in an aqueous solution of hydrophilic polymer saline (pH >; 7) in an appropriate mold. The mold is placed in a freezer / lyophilizer to produce a hydrophilic sponge reinforced with neutralized chitosan sponge. The subsequent mixed material sponge is then compacted to an appropriate thickness. One form of highly preferred cylindrical sponge material is that in which the sponge is formed within a wet textile fiber. The diameter of the sponge and fiber is typically 1-2 mm. The compression of this fiber, normal to its axis, results in a fiber impregnated with flexible chitosan of 0.2 to 0.5 mm in diameter that can be woven as a highly elastic medical bandage tape for administration to internal bleeding lesions and injuries that require superposition, and manipulation of multiple lacerated sites to control bleeding. Said tape can be extremely convenient for stratification in wounds of varying degrees of severity including those that are orthogonal. The impregnated polymer in the tape can accelerate local coagulation as well as firm adhesion to the tissue. A fiber impregnated with chitosan of this type can provide accelerated coagulation in individuals with compromised normal platelet coagulation such as hemophiliacs and people in shock. The sponges of the invention can be coupled and secured using mechanical means. Specifically, the side of the sponge that will be in contact with the wounds and tissue of the individual during use can be pressed against a micro-textured surface. The micro-textured surface may include, but is not limited to, surfaces prepared by mechanical cutting and surfaces prepared by laser ablation. The mechanical traction of the sponge can also be improved by pressing the surface of the sponge that will be in contact with the wounds and tissue of the individual during use against a macro-textured surface. The macro-textured surface may include, but is not limited to, surfaces that are prepared by chemical etching, and surfaces that are prepared by particle blasting techniques. The sponge may comprise a textile fiber impregnated with a hydrophilic polymer. The fiber can be any material, synthetic or natural, that can absorb the hydrophilic polymer. For example, fiber can be a material of plant origin. Preferably, the fiber has multiple filaments. The sponge dressing can have a backup support layer attached to it that provides and facilitates improved mechanical properties and handling. This backing layer can be attached or attached to the dressing by direct bonding with the top layer of chitosan, or an adhesive such as 3M 9942 acrylate-based skin adhesive, or fibrin-based or glue based adhesive can be used. of cyanoacrylate. This backup support layer is also preferably substantially insoluble in blood. The backup support layer is also preferably substantially impermeable to blood. The backup support layer is also preferably substantially biodegradable. The backup support layer is preferably a material, which allows firm handling of the bandage during application and non-adhesion to the hands once the bandage is applied. Preferably, the material forming the backing support is a layer of polymeric material. Examples of preferred backing materials include meshes and / or films and / or low modulus warps of synthetic polymers and of natural origin. Synthetic biodegradable materials can include, but are not limited to, poly (glycolic) acid, poly (lactic acid), poly (e-caprolactone), poly (β-hydroxybutyric acid), poly (β-hydroxyvaleric acid), polydioxanone, poly (ethylene oxide), poly (malic) acid, poly (tartronic acid), polyphosphazene, polyethylene copolymers, polypropylene copolymers, and the copolymers of the monomers used to synthesize the aforementioned polymers or combinations thereof. Biodegradable polymers of natural origin can include, but are not limited to, chitin, algin, starch, dextran, collagen and albumin. Non-biodegradable polymers for temporary applications in external wounds include polyethylene, polypropylene, metallocene polymers, polyurethanes, polyvinyl chloride polymers, polyesters, polyamides or combinations thereof. The dressing of this invention has the degree of adhesion to the wound site which is preferably at least about 40 kPa, more preferred at least about 60 kPa, and most preferably at least about 100 kPa. In addition, the dressing has a thickness that is preferably not less than about 3.0 mm, more preferred not less than about 3.5 mm, and more preferred still not less than about 4.0 mm, and preferably not more than about 8.0 mm, more preferred not greater than about 7.0 mm, and more preferred not even greater than about 6.5 mm. The apposite (2.5 cm wide) of this invention preferably has a final tensile breakage load of not less than 1 kg, more preferred at least 1.5 kg and more preferred still at least 2.25 kg. This same dressing preferably has a final stretch of at least 5%, more preferred at least 10% and even more preferred at least 15%. The Young's modulus of this apposite preference is less than 10 MPa, more preferred less than 3 MPa and more preferred still less than 1 MPa. The dressing preferably includes a complementary traction surface which is particularly useful for applying the dressing to a wound site that includes a significant amount of surface blood. The complementary traction surface may comprise at least one outer surface that holds the site of the wound to prevent sliding of the dressing, typically in a direction opposite to that of the wound site, during use. The complementary traction surface is preferably in the form of a groove design (tread). The dressing of the present invention can form an adhesive material in combination with blood flowing from said wound at the blood-dressing interface. In this case, the chitosan-based adhesive material preferably has a pH of no more than about 5.5, more preferred no greater than about 4.5, more preferred no greater than about 4, when the wound is sealed. The typical acids used for the purpose of adjusting the pH of the chitosan dressing are the following: acetic acid, formic acid, lactic acid, ascorbic acid, hydrochloric acid and citric acid. The molar ratio of acid anion to glucosamine functional groups in the cation / anion moiety of chitosan to adjust the pH to the level described above is preferably about 0.90, more preferred about 0.75, and even more preferred about 0.60.

The dressing can be configured to the configuration of the wound to make contact in a form coupled to the wound, and to facilitate the arrest of the flow of profuse, severe bleeding. More particularly, the dressing is inserted into the interstices of the wound. More preferably, the dressing can be adjusted in a tubular configuration. Then, the reconfigured dressing is inserted into the wound. This invention also contemplates a method for controlling profuse, severe bleeding from a wound at a person's wound site. The method comprises providing a dressing formed from a biomaterial comprising chitosan, adhering said dressing to the wound site and substantially stopping the flow of said severe, profuse bleeding from said wound. Preferably, the wound is sealed and bleeding is prevented from said wound site. Also, bleeding and the flow of other fluids inwardly and / or away from said wound site are preferably avoided. The dressing of the invention acts to rapidly produce a strong clot at the site of the hemorrhage by agglutination of the erythrocytes. It can also promote coagulation by accelerating the normal platelet clotting pathway. In some applications, the rate of dissolution of the present dressing is relatively slow compared to the speed of agglutination, and this equilibrium produces good results, because high-speed agglutination stops dissolution. This demonstrates the importance of the uniformity of the internal and superficial structure of the dressing. If a substantial defect in the dressing is present, such as a channel caused by grain boundaries or minor cracking, then significant blood flow forms a channel along the defect and produces a highly undesirable bleeding leak condition, which It can leach the smaller and less viscous agglutination areas as they form. In addition, it appears that significant blood flow under pressure on the surface of the wafer adversely affects the adhesion of the dressing wound of the prior art, but not adhesion to the wound of the dressing of this invention. An important preferred attribute of the dressing of the invention is the means for combining the chitosan with the blood, while at the same time achieving the mechanical integrity of the resulting "clot" and the binding of the clot to the surface immediately adjacent to the lesion. The dressing of the present invention accelerates the formation of blood clot at the site of the wound, reinforces clot formation at the wound site and prevents bleeding from the wound site. It also substantially prevents the flow of blood and other fluids in and / or out of the wound site. The dressing of the present invention maintains its double capacity for coagulation and adhesion to a wound site while exhibiting a high level of elasticity in an extreme environment. The remarkable elasticity of this apposite is exemplified by the formidable physical properties of the dressing. The dressing of the present invention, unlike the prior art products described above, also has a remarkable ability to conform to the shape of the wound while maintaining structural elasticity. This structural elasticity allows the dressing to assume a preferred shape after deformation, without any substantial loss of mechanical properties. Preferably, the dressing for hemorrhage control of the invention includes a surface that holds the area of the wound to substantially prevent the dressing from slipping during use. Typically, this non-slip surface of the dressing comprises a traction surface. The hemorrhage control dressing of the present invention can benefit from having an effective non-slip surface, such as a traction surface. The dressing for hemorrhage control of the present invention may have a smooth side and a rough side. The rougher side is preferably the side of the surface for tissue or bleeding, if said side also shows better adhesive properties. A traction surface can improve the ability of the dressing to control rapid arterial bleeding by providing increased stability of surface contact (more adequate traction) on a well-lubricated surface (such as those surfaces that occur in the case of severe bleeding). Said traction surface helps to channel the blood, without adversely affecting the adhesion kinetics while allowing a more controlled and stable tissue contact during the critical period of apposition application. For example, the tissue side of the bandage may have a traction surface in the form of a groove design. This groove design can prevent the dressing from experiencing loss of traction in a direction opposite to the wound when applied to the wound. The non-slip surface of the dressing for bleeding control can be produced with grooves that are not connected or hidden from each other. In this way, in turn, the channels formed between the ridges can be completely or partially hidden from one another and thus provide a controlled connection that can provide controlled blood flow back to or out of the injured area. Controlled blood flow in the area of application of the dressing can be maintained by striations or specific types of gates with responsiveness in the bleeding control dressing. Stretch marks at the bottom of a mold for producing the dressing for hemorrhage control may include depressions of the type permitting a non-slip surface, for example, in the form of traction controls such as projections or the like, in the dressings of the present invention. . Therefore, a dressing for hemorrhage control having at least one non-skid surface, such as a traction surface, can be produced. In addition, a method for producing said apposite can be provided. Finally, a mold can be made to produce a dressing for bleeding control. To treat severe hemorrhages in cases where the base and top adhesive surfaces are convenient, it is possible to design the support backing so that it can be easily peeled off when adhesion and coagulation are required on both surfaces. There are numerous configurations for bleed control of the dressings to address a wide variety of possible types of hemorrhagic wound. Several bandages of different configurations may be necessary (for example, in a battlefield situation) so that injured persons can be treated by the first person to respond or even by persons also injured. The dressing of the invention can tolerate a large amount of physical abuse and still remain a platform for control of active bleeding. The dressing is ideal for treating focal vascular bleeding as well as small topical wounds. It is also suitable for filling complex entry wounds in cases where the bleeding site can not be easily compressed. Once control of bleeding is achieved with the present invention, the stabilization of a wound in the limb, bringing the edges of the wound closer together and creating a durable dressing that avoids contamination and allows the evacuation of the injured person for a definitive cure are the main requirements for a dressing for control of bleeding for civilians and on the battlefield. One contemplated configuration of the bleeding control dressing is a 25.4 cm x 45.72 cm dressing with a resilient, flexible backing that can be tightly joined around a limb and secured with a holding tab such as a permanent adhesive glue via a back surface. removable. This configuration can approximate the wound surfaces and add a hemorrhage control surface without compromising blood flow to the distal extremity, and can be applied by the first person to respond or in some cases by the injured soldier and can be stable under ambulatory or limb movement during transport. It is contemplated that the bandage can be removed by cutting it without adverse adhesion to the wound or skin.

B. Methods for making compressed sponges and compressed mixed material sponges A method is provided to produce a dressing that can control heavy, profuse bleeding from a wound at a person's wound site. Said method comprises the steps of providing bio-material based on chitosan as described above. The steps to produce the structure or shape are typically made from a solution and can be achieved using techniques such as freezing (to cause phase separation), die extrusion without solvent (to produce a filament), electro-spinning ( to produce a filament), phase inversion and precipitation with a non-solvent (such as is typically used to produce filter and dialysis membranes) or solution coating on a woven or pre-formed sponge type product. In the case of freezing, in which two or more different phases are formed by freezing (typically the water freezes to form ice with differentiation of the bio-material based on chitosan as a separate solid phase), another step is required to eliminate the frozen solvent (typically ice), and thus produce the dressing without disturbing the frozen structure. This can be achieved by a lyophilization step and / or a freeze replacement step. The filament can be configured as a protected sponge type mesh using non-woven spinning processes. Alternatively, the filament can be produced as a felted warp by conventional spinning and weaving processes. Other methods that can be used to make such a bio-material sponge-like product include dissolving pore-forming agents from a solid chitosan matrix or drilling material from said matrix. Preferably, the chitosan material is de-gasified from general atmospheric gases. Typically, degassing is the removal of sufficient residual gas from the chitosan-based bio-material such that, upon being subjected to a subsequent freezing operation, the gas does not escape and forms unwanted voids or large trapped gas bubbles in the apposition product of the present invention. The degassing step can be effected by heating a chitosan-based bio-material, typically in the form of a solution, and then applying a vacuum to it. For example, degassing can be effected by heating a chitosan solution to approximately 60 ° C immediately before applying vacuum to approximately 500 mTorr for about 5 minutes while stirring the solution. One method of treating the sponge solution of hydrophilic polymeric bio material is to add some gases back to the solution after the initial degassing. Such gases may include but are not limited to, argon, nitrogen and helium. An advantage of this step is that solutions containing partial pressures of these gases form micro-voids upon freezing. The micro-hole is carried through the sponge as the ice front advances. This leaves a well-defined and controlled channel that helps the sponge's pore interconnecting capacity. Next, the chitosan bio-material, which is typically in the form of a solution, is subjected to a freezing step. The freezing is preferably carried out by cooling the bio-material solution of chitosan and reducing the temperature of the solution from room temperature to a final temperature below the freezing point. In this way, the preferred structure of the dressing product can be prepared. The final freezing temperature is preferably no greater than about -10 ° C, more preferred no greater than about -20 ° C, and more preferred still not more than about -30 ° C. Preferably, the temperature is gradually reduced over a predetermined time interval. For example, the freezing temperature of a solution of bio-material of chitosan can be lowered from room temperature to -45 ° C by applying a constant temperature cooling ramp of -0.4 ° C / min to -0.8 ° C / min. min approximately during an interval of 90 minutes approximately until 160 minutes approximately. The frozen chitosan bio-material can then be subjected to water removal from the interstices of the frozen material. This step of water removal can be achieved without damaging the structural integrity of the frozen chitosan bio-material. This can be achieved without producing a substantial liquid phase which can alter the structural arrangement of the final dressing. Therefore, the bio-material of chitosan passes from a solid frozen phase to a gaseous phase without the substantial formation of intermediate liquid phase. The preferred way to implement water removal is by using a lyophilization step. The lyophilization of the frozen chitosan bio-material can be effected by additionally freezing the frozen chitosan bio-material. Typically, vacuum is then applied. Next, the non-frozen chitosan material subjected to vacuum can be heated. Then, the chitosan material frozen, subjected to vacuum, heated preferably dried. More specifically, the frozen chitosan bio-material may be subjected to subsequent freezing preferably at about -15 ° C, more preferred at about -25 ° C, and even more preferably at about -45 ° C, over a range of preferred time of at least about 1 hour, more preferred at least about 2 hours, and most preferably at least about 3 hours. This step can be followed by cooling the condenser to a temperature of less than about -45 ° C, more preferred to about -60 ° C, and even more preferred to about -85 ° C. Then, a vacuum may preferably be applied in an amount of about 150 mTorr at most, more preferably about 100 mTorr at most, and most preferably at least about 50 mTorr. Then, the frozen, evacuated chitosan material can be heated preferably to about -25 ° C, more preferred to about -15 ° C, and even more preferably to about -10 ° C, during a preferred time interval of less about 1 hour, more preferred at least about 5 hours, and most preferably at least about 10 hours. Finally, the drying may preferably be carried out at a temperature of about 20 ° C, more preferred at about 15 ° C, and even more preferred at about 10 ° C, for a preferred time interval of at least about 36 hours , more preferred at least about 42 hours, and more preferably at least about 48 hours. Subsequently, the bio-material of chitosan can be compacted, for example using heated platens to reduce the thickness and increase the density of said dressing. The compaction temperature is preferably not less than about 60 ° C, more preferred is not less than about 75 ° C and not more than about 85 ° C. Then, the compacted biocomposite bio-material is preferably pre-conditioned by preferably heating to a temperature of up to about 75 ° C, more preferred to a temperature of up to about 80 ° C, and more preferably still preferred to a temperature of up to 85 ° C. Pre-conditioning is typically carried out for a time interval of up to about 0.25 hours, preferably up to about 0.35 hours, more preferred up to about 0.45 hours, and even more preferred up to about 0.50 hours, thereby increasing the adhesion strength and resistance to dissolution of said dressing, as described above. The processed dressing can then be subjected to a sterilization step. The dressing can be sterilized by a number of methods. For example, a preferred method is by irradiation, such as by gamma irradiation, which may also increase resistance to blood dissolution, tensile properties and adhesion properties of the dressing. The irradiation can be carried out at a level of at least about 5 kGy, more preferred of at least about 10 kGy, and more preferably at least about 15 kGy. The sterilized dressing can then be packaged for storage in a thermally sealed bag, purged with an inert gas such as either argon gas or nitrogen. A dressing is produced from the bio-material of chitosan, which can substantially retain the flow of profuse, severe bleeding from a wound by adhesion of the dressing to the wound site. The dressing preferably seals said wound and prevents the exit of blood from said site of the wound by adhering said dressing to said wound site using coagulation and agglutination of severe bleeding. This dressing preferably adheres strongly to the site of the wound, while coagulating and agglutinating the erythrocytes around the wound, so that only pressure needs to be used preferably in the first five minutes of application. In one form of this invention, the device is designed to be a temporary dressing that is applied, even by unqualified practitioners, in order to keep the injured person alive until the experienced medical intervention is possible.

C. Active agents used in compressed sponges The compressed sponge may also comprise an active ingredient. The active ingredient can be, but is not limited to, human serum albumin, calcium, bovine thrombin, human thrombin (hThrombin), rh Thrombin, factor Vlla, factor XIII, recombinant Factor XIII (rFactor XIII), thromboxane A2, prostaglandin-2a epidermal growth factor, platelet-derived growth factor, von Willebrand factor, tumor necrosis factor (TNF), TNF-alpha, transforming growth factor (TGF), TGF-alpha, TGF-beta, growth factor insulin type, fibroblast growth factor, keratinocyte growth factor, nerve growth factor, penicillin, ampicillin, ethicillin, amoxicillin, clavamox, clavulanic acid, amoxicillin, aztreonam, imipenem, streptomycin, kanamycin, tobramycin, gentamicin, vancomycin, clindamycin, erythromycin, polymyxin, bacitracin, amphotericin, nystatin, rifampicin, tetracycline, doxycycline and chloramphenicol, or combinations thereof depending on the nature of the wound or of the patient's medical condition. For example, wounds received in a military setting may comprise an antibiotic, an anti-fungal, and a coagulation factor. Patients with cancer in surgery may receive a different combination of active agents.

EXAMPLE 1 Evaluation of bleeding control Table 1 provides a list of the main materials of chitosan purchased for the evaluation of hemorrhage control. With the exception of the Gelfoam ™ + thrombin, and Surgicel ™ controls for porcine spleen experiments and the 10.16 cm x 10.16 cm gauze control of Johnson and Johnson for use in porcine aortic perforations, the dressing materials described in the present invention They are all based on Chitosan.

TABLE 1 10 * Below the accepted limits of lead, mercury, bismuth, antimony, tin, cadmium, silver, copper and molybdenum. NA = not available fifteen Aqueous solutions (2.00% by weight) are prepared in sterile, clean, 1 liter Pyrex flasks, from Ametek, ultra-filtered water (UF) and dry chitosan. In the case of Carbomer, Primex and Genis chitosan materials, 1.0% or 2.0% by weight of glacial acetic acid (Aldrich 99.99%) is added to the aqueous mixtures. The dissolution is achieved by shaking the flask at 40 ° C for 12 to 48 hours. The solutions are degassed by application of vacuum at 500 mTorr at room temperature immediately before freezing. The dressings are prepared from 2% aqueous solutions of chitosan that are poured into aluminum or polyethylene molds coated with Teflon ™ until at least 1.5 cm deep and frozen in a Reveo freezer from -80 ° C to - 45 ° C for 3 hours. Alternatively, the freezing is done on the interior shelves of a Virtis Gen 35EL freeze dryer. There is almost 10% shrinkage in the dressings and the density of the lyophilized final dressing is close to 0.033 g / cm3. Figures 1 and 2 show cross sections of two types of molded apposites (different freezing speeds). The structures observed (figure 3) are affected by the cooling rates in the bulk solution and in the different surfaces. Subsequently, the structures in the dressings are controlled by formulation, mold (size and shape) and freezing conditions. The optimal dressing structures are those that are open pore consisting of pores connected together, uniform, close to 50 microns in diameter or lamellae and hexagonal structures normal to the plane of cooling. These structures can be controlled, producing flexible but strong pockets of large specific surface areas for highly efficient and rapid blood coagulation. Typically, the specific surface area available for said structures is greater than 500 cm2 / g. The electron scanning photomicrograph in Figure 5 shows the typical open cell structure in the base surface of a dressing. The dressings are heated in a convection oven at 80 ± 1 ° C for half an hour to optimize the structure and distribution of acetic acid concentration. It has been found that this step is essential to optimize the adhesive properties of the dressings in a hemorrhage zone (typically adhesion to the dermis >).; 40 kPa). The dressings are immediately compacted from 17 mm thick to 5.5 ± 0.5 mm at 80 ± 5 ° C under a load close to 50 kPa (from a density of approximately 0.03 ± 005 g / cm3 to 0.12 ± 0.02 g / cm3).

Figure 4 shows the appearance of the base of a typical preferred chitosan dressing for control of bleeding after heating and compression.

EXAMPLE 2 Preparation and evaluation of the dressing Haemostatic dressings are prepared as follows: a) Dry chitosan powder or flakes with a degree of deacetylation greater than 85%, less than 25 ppm of metal component and more than 90% dry solids content are used to prepare a 2% aqueous solution (by weight) with acetic acid approximately 2% or 1% (by weight) at 40 ° C. b) The chitosan solution from (a) above is degassed at reduced pressure of up to 500 mTorr approximately under agitation for at least 5 minutes and is poured into a mold to a depth of 1.7 cm. Some of the low density foam structures present problems due to their easy dissolution in a hemorrhage zone. These problems are usually avoided by complete de-gasification of the solution. c) The mold containing the degassed chitosan solution is frozen by cooling from room temperature to -45 ° C. It is used to a linear cooling trap over a period of 90 minutes, and the temperature is maintained at -45 ° C for at least another hour. d) The frozen chitosan is then lyophilized using a condenser that is at a temperature below -70 ° C and at a vacuum of about 100 mTorr. The shelf temperature is increased from -45 ° C to -15 ° C and maintained at that level for 10 hours. Then an additional 36-48 hours of lyophilization is carried out at 10 ° C. Lyophilization is carried out until about 2.8% of the original frozen plate mass is obtained. e) At 2.8% of the original mass, the procedure is stopped, and the lyophilized dressing is removed from the mold. f) The product formed is a dressing with a specific surface area, soluble in water, regulated with acid that presents a shrinkage of 10% of its original frozen volume. The structure of the dressing is generally a uniform open pore structure with pores that connect to each other from 50 to 80 microns in diameter. Using a slightly different cooling regime in which supercooling is not affected, a lamella / hexagonal structure is obtained (with uniformly thin chitosan sheets close to 5 microns thick with a separation of about 50 microns between the sheets) . g) The dressing is then compacted (from 1.7 cm to approximately 0.5 cm thick) between smooth and flat plates with a temperature of 80 ± 2 ° C under application of 60 +20 kPa of pressure. Next, the dressing is conditioned in a convection oven by heating at 80 + 5 ° C for 30 minutes. i) Each dressing is then stored in bags Kapak 530 marked, thermally sealed. j) The resulting compacted dressing is hard, flexible, hemostatic, adherent to the moist tissue and resistant to dissolution by the flowing blood. k) Improved dissolution properties, improved adhesion resistance and sterilization are achieved by exposing the dressing to 15 kGy of gamma irradiation under a nitrogen atmosphere. The in vivo evaluation of haemostasis of the dressings for control of hemorrhage candidates of composition and variable structure is analyzed in increasingly challenging animal models of hemorrhage. A splenic laceration model is used in order to evaluate large numbers of candidate dressings in a simple reproducible model and to compare them with conventional materials. Although this is the least challenging bleeding model (bleeding with light exudation of approximately 2-5 ml / minute), most initial dressing formulations do not pass this test. In addition all gels, chitosan powder, do not pass this test while the films show a very low performance. Prior to evaluation in a severe hemorrhage model, coagulation in pigs is avoided by systemic intravenous heparin and the best materials are evaluated in an encapsulated spleen denudation model. (bleeding with intense exudation of approximately 10-20 ml / minute). Those few materials that pass this test are then evaluated in the carotid laceration model (approximately 50 ml / minute) in pigs treated with anticoagulant. The formulations for dressing of candidate materials that pass this test are then evaluated in the porcine aortotomy model in which perforations of 4 mm in diameter are made in the thoracic or abdominal aortas. The materials that pass these challenge models of severe vascular hemorrhage (bleeding velocities greater than 100 ml / minute) are also evaluated in a severe model (grade V) of hepatic trauma. The evaluation is carried out on healthy animals that have previously undergone the procedures and are scheduled to be sacrificed for evaluation. All experiments are carried out in accordance with the National Research Council's Guide for the Care and Use of Laboratory Animal of 1996 and the applicable federal regulations. After identifying the animal, anesthesia is induced with telazol at 4-9 mg / kg intramuscularly (i.m.). Isoflurane is administered by mask and the animal is intubated. The chitosan patches for capsular denudation laceration experiments can be square pieces of equal size cut from a 37 mm diameter dressing or 1.5 cm x 1.5 cm dressing pieces cut from a larger dressing. The control materials of Gelfoam ™ + thrombin or Surgicel ™ are prepared from pieces of 1.5 cm by 1.5 cm. Gelfoam ™ absorbable gelatin size 100, is supplied by Pharmacia. Oxidized cellulose, Surgicel ™ is supplied by Ethicon. Topical thrombin (of bovine origin) 10,000 US units is supplied by Jones Pharma. Gelfoam ™ + Thrombin is prepared before use by dipping 1.5 cm x 1.5 cm x 0.8 cm dressings into the thrombin for 30 minutes. A midline ventral laporate is performed. The upper half of the spleen is exteriorized (joining the surgical wound with towel tongs). The surface is kept moist by the application of sterile saline from a wet lap pad. For anti-coagulation, the right femoral artery is surgically isolated and a cannula with a 6F sheath is applied, which allows the cction of blood sample. Activated clotting time (ACT) is measured before administration of 5000 units of heparin intravenously, 10 minutes after administration of heparin and every 20 minutes thereafter. If the ACT level is less than 200 seconds, 2000 units of heparin are administered and the ACT is re-measured after 10 minutes. This is repeated until the ACT is > 200 seconds to ensure that the animal does not have coagulation. The evaluation area in the spleen is marked and kept moist using the towel tongs and the wet pads and exposing only the most immediate non-evaluated surface. A single lesion is performed before the application of a test patch, as fws: (i) in the laceration model, the lesion (8 mm long x 4 mm deep) is made using a # 11 scalpel positioned in forceps at right angles so that 4 mm of the blade are projected. (ii) in the capsular denudation model, the lesion (5 mm x 5 mm by 4 mm deep) is made using the # 11 scalpel and a pair of surgical scissors. After performing the injury, bleeding is allowed for 30 seconds. The surface blood is removed with gauze, after which a test patch is digitally applied to the lesion using a constant uniform pressure for 30 seconds. Then the digital pressure is removed and the patch is observed for 2 minutes. In this stage, the test number is recorded. If an observable re-bleed occurs, the time to re-bleed is recorded, and the next trial begins (30 seconds of bleeding, the blood is cleaned with gauze, 30 seconds of digital pressure followed by up to 2 minutes of observation). The test for a test patch is completed when there is no re-bleeding in the observation period of 2 minutes or of 6 if re-bleeding of the test is observed. If the wound continues to bleed for 6 trial periods, then the patch that did not work is removed and a Gelfoam + thrombin patch is applied. A new lesion is made and another patch is evaluated. In the case of the carotid laceration model, patches of chitosan (37 mm x 25 mm) are cut from the 37 mm diameter compressed dressing or larger apices. For ease of application, some of the dressings have a 13M 9781 medical tape top tape attached to the chitosan with 3M 9942 skin adhesive. The Gelfoam ™ + thrombin is used as a control. A vertical incision is made exposing a length of 10 cm of carotid artery. The fascia is retracted and the surrounding soft tissue is dissected until the artery is supported on a flat tissue base. Sutures are attached proximal and distal to the exposed artery. This is held with pliers and an incision of 1.5 cm is made longitudinally in the artery. For anti-coagulation, the right femoral artery is surgically isolated and a cannula with a 6F sheath is applied, allowing collection of blood samples. The activated clotting time (ACT) is measured before the administration of 5,000 units of heparin intravenously, 10 minutes after the administration of heparin and every 20 minutes thereafter. If the ACT level is less than 200 seconds, 2000 units of heparin are administered and the ACT is re-measured after 10 minutes. This is repeated until the ACT is >; 200 seconds to ensure that the animal has anti-coagulant. After the incision is made, the artery is allowed to bleed for 2 seconds and then compressed for 1 minute. The compression is removed and the ligatures are restrained. The area is rinsed with saline. The ligatures are released 2 seconds before the application of a patch. Pressure is applied evenly on the patch for 3 minutes. If bleeding is observed within 30 minutes after the application of pressure, then another 3 minutes of pressure is applied again. If the patch does not stick, then it is replaced with a new patch. Each new application of pressure, or replacement of a patch of the same type is treated as trial periods for that type of patch. An assay for a particular dressing is considered complete if bleeding is not observed around the patch or within 30 minutes. The material is classified based on the number of trials it took to achieve 30 minutes of hemostasis (without observable bleeding of the wound). In the case of porcine aortic perforation, sample patches of chitosan apposites cut into pieces of 2.5 cm in diameter or controls of 10.16 cm x 10.16 cm of surgical gauze are used. Either or both of the abdominal and thoracic aortas are exposed by ventral laporatomies of the central line in the case of the first and sternotomies in the case of the latter. The fascia and sternum are fastened with pliers and proximal and distal ligatures are placed at the incision sites. While applying the holding pliers, a # 11 scalpel blade is used to make a 3-mm incision through the wall of the aorta and a Medtronic ™ 4 mm diameter vascular punch is inserted through the incision to make a 4 mm diameter hole in the aorta. The punch is removed and the clamping tongs are released by applying digital pressure to the hole. The patch is held between the thumb and forefinger and the middle finger is used to apply pressure to the hole in the aorta. The pressure of this middle finger is released for 1 second before applying the dressing to the area of bleeding. The dressing is held in place by firm pressure applied through the middle finger to the patch through the aortic foramen. Mixed blood escaping from the wound during application of the patch is removed by suction. After 3 minutes of digital pressure, the finger is removed and the patch is inspected for any sign of continuous bleeding and poor adherence. If continuous bleeding or rebleeding is observed in the first 30 minutes after applying the patch, then 3 additional minutes of pressure will be applied. If the hemostasis is not yet complete, then another patch of the same dressing is prepared, the used patch is removed and a new trial begins. An assay is considered complete if bleeding is not observed in the surroundings or through the patch within 30 minutes. The material is classified based on the number of tests that it takes to achieve 30 minutes of hemostasis (without observable bleeding of the wound). The gauze control samples are applied in the same manner as the chitosan dressing during a test. All animals are euthanized while anesthetized with an injection of barbiturates [Euthasol, 0.22 ml / kg (1 ml / 10 pounds)] through an atrial vein. The animals are euthanized at the end of the experimental procedure or before the end if the animal experiences any effects of resistance to manipulation. The tests are classified from 0.0 to 6.0 in accordance with the number of trials required before bleeding control is achieved and the time to bleed again (only in the case of spleen tests). A test in which only one trial is necessary and no re-bleeding is scored as 0.0. A test that requires a second test and the time to re-bleed from the first is 90 seconds is scored as: 120-90 1.0 H = 1.25 (in the case of a spleen) or 1.0 in the other 120 models A test that requires four trials to achieve hemostasis and in which the time for re-bleeding of spleen in the third trial is 30 seconds is Qualify: 120-30 3.0 + = 3.75 120 (in the case of a spleen) or 3.0 in the other models. A sample that fails completely due to rapid dissolution, lack of adherence or uncontrolled bleeding is rated as 6.0+. In summary, the more deficient the hemostasis, the higher the qualification as defined by the following: R = r +? in which r = number of trials to stop the bleeding-1 _ _ A - time for the (ies) test (s) in the previous test A = trial time or trials The results of the spleen studies are presented in summary form in Tables 2, 3 and 4. Table 2 illustrates the behavior of chitosan test samples that are not optimized with respect to composition and structure. These non-optimized materials range from, "worse" for the Surgicel ™ negative control (table 4), to comparable and even only partially better. The presence of a phosphate buffer produces a slowly haemostatic patch that is not vadherent and is only slightly more effective than Surgicel ™. The chitosan film is moderately adherent, providing a reasonable seal to bleeding, however this is only vslowly hemostatic as demonstrated by the slow accumulation of blood below its transparent surface. Initial tests usually show signs of a low density foam on the upper surface of the molded dressing. It has been found that this low density foam is susceptible to dissolution and collapse if the top surface of the dressing is applied to a bleeding zone. It was subsequently discovered that this foaming effect can be avoided by degassing the solutions before freezing them. It was found that the low molecular weight chitosan dressings (relative viscosity of the 1% solution < 50 cps) are vsusceptible to dissolution in a bleeding zone which makes them unsuitable for patch application. The contra-anion glutamate produces softer apposition but at the expense of producing apposition that dissolves easily in an area with vheavy bleeding. It was also found that low density apposites (those less than 0.05 g / cm3) with acetate counter-ions are easily compromised by dissolution and collapse. Table 3 shows the results scores of optimized chitosan dressings of the preferred composition and structure. These apposites are constituted by chitosan with higher molecular weights (relative viscosity of 1% solution higher than 100 cps) and have apposition densities close to 0.12 g / cm3. In the spleen tests with moderate bleeding, it is found that the results for the optimized dressings, using the Wilcoxon rank sum test W, are indistinguishable from the positive control of Gelfoam ™ + thrombin (Z = -0.527, p = 0.598) . Using the same statistical method, it is demonstrated that the apposites are significantly different from the Surgicel ™ control with vpoor performance (Z = -3.96, p = 0.0001). Figure 6 demonstrates (through a histological section stained with H and E) the close adherence of optimized chitosan patch patches to the surface of the spleen as well as the agglutination of hrocytes in the immediate vicinity of the lesion. The qualifications for the carotid injury model are presented in summary form in Table 5. In this model, the optimized chitosan patch performs quite adequately in trials 3, 5 and 6. The improvement in performance with with respect to the first tests 1 and 2, it is due to the application of the support backing (foam bandage 9781 from 3M) to the immediate upper surface of the dressing. This backing allows more uniform pressure to be applied to the dressing and allows the person applying the dressing to remove it from their fingers easily from the surface of the patch without adhering them and inducing the detachment of the patch from the wound. The carotid model is used to investigate more severe arterial bleeding conditions than those that are possible in the spleen injury model. Gelfoam ™ + thrombin is investigated as a possible positive control but it is discovered that it dissolves in an area with very heavy bleeding. Table 6 summarizes the results of the aortic injury model. Gauze bandage (10.16 cm x 10.16 cm) is used as a control bandage. It is discovered that control can not stop severe bleeding at all trial periods while optimized chitosan aortic patches can stop and then quickly coagulate the very high level of bleeding observed in this wound after only 1 or 2 applications of the patch . The exact significance (p = 0.002 of two tails) is determined for the probability that there is no difference between the scores of the sample and the control. On average, the blood loss after applying the patch is minimal (<; 50 ml) if the wound stops (stanched) on the first attempt. If a second attempt is required, the blood loss after application of the patch is greater than 100 ml but less than 300 ml. On average, less than 150 ml of blood is lost after each patch application in the case of chitosan dressing, while in the case of the 3 gauze control studies, more than 1 liter of blood is lost for each animal. In the case of chitosan dressing, the survival is 100%, while in the case of gauze, none (0%) of the animals survive. The chitosan patches demonstrate continuous hemostatic efficacy throughout the 30-minute test period and until the animals are sacrificed which usually occurs 1 to 2 hours later. Figure 7 demonstrates a typical chitosan patch that seals a severe chest wound. Figure 8 shows the side of the lumen (showing the wound) of the excised aorta sealed by the patch in Figure 7. Figure 9 shows a photomicrograph of a stained histological section taken through the lesion of Figures 7 and 8. Evidence of strong coagulation at the wound site is found by excising and inspecting the aortas during the slaughter of the animal (Figure 9) and, in the case of trial number 16, in which after evicting a patch in a live animal (after more than 30 minutes of application) there is no subsequent re-bleeding.

TABLE 2 10 Dense type = dense apostrophe (approximately 0.12 g cm) Trat. with PBS = a neutralized dressing by immersion in phosphate-buffered saline Type LD = low density dressing (approximately 0.03 g / cm3) Type FF = a fast freezing dressing Type of film = a film emptied with solvent (500 microns) fifteen TABLE 3 TABLE 4 10 fifteen TABLE 5 Animal Number Batch Name Source of Classification AntiModel Form Comments of sample shows sample shows coagulant sample result lesion results model test 1404 Chitosan Primex Chitoclear BN 381 Dense Type Si Laceration First trial injury. Deep bleeding at the site before application, first three applications slow the bleeding, the final application closes the wound area not covered initially 1335 Quitosana Primex Chitoclear TM 752 Dense Type Yes Laceration Sample without backing. Problems with the application of pressure without damaging the dressing in the area of bleeding 1335 Quitosana Pronova CL213 Si Laceration The 3M backing allows the application of 10 pressure without damaging the dressing 1442 Quitosana Primes Chitoclear Si Laceration 0 Backing 3M + good adhesion and rapid haemostasis 1442 Chitosan Primes Chitoclear Si Laceration 1 3M backing + good adhesion and rapid hemostasis 1441 Chitosan Pharmacia Gelfoam + th Si Laceration 6+ Can not stop bleeding due to Gelfoam dissolving in the area of bleeding and not adherent Dense type = dense sponge dressing (approximately 0.12 g / cm) 15 TABLE 6 10 15 TABLE 6 (cont.) 10 15 TABLE 6 (cont.) 10 15 EXAMPLE 3 Control of hepatic hemorrhage in porcine liver model The Control of Hemorrhage, Objective of Science and Technology (STO) A, of the Army of the United States of North America, was established in the year 2000 to try to solve the need regarding control of hemorrhage in the battlefield. The overall strategic objective of the STO can be summarized as the development of products and methods that reduce the number of deaths due to hemorrhages in casualties on the battlefield. The requirements for products and methods for hemorrhage control are listed in this way: These should be practicable for use by one or more of the following: self (wounded combatant), companion (non-medical escort soldier assisting wounded soldier) , combat lifeguard, combat medic, medical assistant, and battalion surgeon. These must be practicable for use in far front conditions, including rugged terrain, limited visibility, and extreme environmental conditions. The products and methods should not require external electrical sources. All devices must be portable and durable. It is expected that products and methods that can be used on the far front can also be used at higher levels of medical care. A specific strategic goal of STO is the development of new or improved hemostatic agents for use in bleeding susceptible to compression under far-field conditions. An individual product is desired for use in sites susceptible to compression or not susceptible to compression. As part of the STO, a control study of hepatic hemorrhage in a porcine liver model is conducted at the Surgical Research Institute (ISR) of the United States Army at Fort Sam Houston, San Antonio, Texas using the bandage for hemorrhage control of this invention. The study is carried out to determine the effect of the bandage for control of chitosan hemorrhage on blood loss and survival in a standardized model of severe venous hemorrhage and liver damage in pigs. This model has been used to study many other hemostatic dressings in the ISR of the Army of the United States of America. In this study, commercial crossbred pigs are used. The animals are kept in a building accredited by the International Association for the Evaluation and Accreditation of Laboratory Animal Care. This study is approved by the Institutional Animal Care and Use Committee of the Army Surgical Research Institute of the United States., Fort Sam Houston, Texas. Animals receive human care in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, publication 86-23, revised 1996). The animals are randomly assigned to receive either chitosan bandages or gauze sponges (see table 7). The surgical preparation consists of the following: the animals are fasted 36-48 hours before the surgical procedure and the water is allowed ad libitum. After pre-dressing with glycopyrrolate and a combination of tiletamine hydrochloride and zolazepam hydrochloride (Telazol®, Fort Dodge Laboratories, Fort Dodge, IA), anesthesia is induced by mask using 5% isoflurane. The pigs are intubated, placed in a ventilator and maintained with isoflurane. Catheters for the carotid artery and the jugular vein are surgically placed. The laparotomy and splenoctomy are performed and the placement of the catheter for the urinary bladder is completed. A rectal temperature between 37 ° C and 39 ° C is required, and 15 minutes of average arterial pressures (MAP) are stable before further experimental procedures. Blood pressure and heart rate are recorded at 10 second intervals throughout the study period using a continuous data collection system ((Micro-Med®, Louisville, KY). Basal samples are collected from each animal to confirm that each animal has a platelet count, prothrombin time, activated partial torbosoplastin time, and normal plasma fibrinogen concentration, and liver lesions are induced.The method includes the following. by manually raising the left and right medial lobes to allow adequate exposure, then a specially designed pair of pliers is positioned with two 4.5 cm sharp tips shaped in an "X" shape, with the center approximately 2-3 cm dorsal to the interception of the left and right medial lobes on the diaphragmatic surface of the liver. it is positioned below the square lobe, on the visceral surface. Attaching the tips of the instrument through the parenchyma and the underlying blood vessels of the two medial lobes so that the tips settle into the corresponding slots in the instrument's base plate. After the first penetration of the liver, the instrument opens and the tips are removed and replaced to the left of the animal so that the second application overlaps the first by 50%. After this re-positioning the liver is penetrated a second time. The documentation of the liver injury is achieved by removing and inspecting the liver at the end of the experimental period. The lesions appear as large star-shaped wounds with a small islet of tissue in the center, and measure approximately 10 x 8 x 4 cm. The lesions pass from one side to the other, lacerating one or more of the left medial lobe vein, right medial lobular vein, and portal vein. Thirty seconds after the injury, resuscitation is started with Ringer's solution with warm lactate (38 ° C) in all animals. The goal of resuscitation is to return to baseline arterial pressures. The fluid is administered at 260 ml / min. This resuscitation regime is continued until the objective is achieved and it is restarted if the MAP decreases, throughout the study period of 60 minutes. Simultaneously with the start of resuscitation (30 seconds after the injury), the treatments are applied as follows. One dressing is applied to the surface of the square lobe to cover the penetrating lesion and the other two apposites are used to fill the lesion from the diaphragmatic aspect. It is applied with pressure for 60 seconds in the back ventral direction. After 60 seconds, the lesion is inspected to determine whether or not hemostasis is achieved. Then the hands of the applicator are re-positioned and pressure is applied for 60 seconds in the latero-medial direction, and observation is made regarding hemostasis. This sequence is repeated for a total of 4 compressions of 60 seconds. If the hemostasis is complete after any compression, no further compressions are made. Hemostasis is defined as the absence of bleeding that can be detected visually from the site of the injury. After completing the treatment application, the abdomen is closed and the animal is monitored for 60 minutes after the injury or until it dies, whichever comes first. Death before 60 minutes is defined as a heart rate of 0. At 60 minutes, the animals that survive are sacrificed by an overdose of pentobarbital. Immediately after inducing the lesion, the blood is continuously suctioned from the peritoneal cavity to the beginning of the application of the treatment. The volume is determined and designated as pre-treatment blood loss. At the end of the study period, each abdomen is opened and the liquid and coagulated intra-peritoneal blood are suctioned and measured. This is designated as post-treatment blood loss. Additionally, the fluid for total resuscitation used is recorded. The blood volume of the animal prior to the injury is calculated in the previously reported manner (Pusateri et al., Mil. Med. 166.217-222, (2001)). Body weight, calculated blood volume, number of lacerated blood vessels, basal MAP, survival time, MAP pre-injury, pre-treatment blood loss, and bandage adherence scores are analyzed by analysis of variance using the GLM procedure of SAS. The data are reported as the least squares of the mean ± standard error of least squares of the mean. The data are examined for heterogeneity and non-normality. These conditions are detected for post-treatment blood loss data and fluid usage. Therefore, the blood loss and fluid usage data are transformed into their logarithms before analysis. The transformed data is analyzed by analysis of variance. These data are expressed as means transformed by regression and 95% confidence interval (95% CI). The distribution data of females and males, hemostasis and survival are analyzed by Fisher's Exact Test using the FREQ procedure of SAS. The data is reported as proportions or percentages. Bilateral tests are used for all comparisons. There are no differences between treatment groups in terms of animal body weight, calculated blood volume, distribution of animal genera, basal MAP, pre-injury MAP, number of major blood vessels lacerated within the liver lesion, or pre-treatment blood loss (see tables 8 and 9). Post-treatment blood loss is reduced in the chitosan group, compared with the gauze dressing control (p = 0.01). There is no significant difference in the use of fluid. The survival percentage increases in the chitosan group (p = 0.04). Hemostasis occurs most frequently in the chitosan group at 3 and 4 minutes after the injury (p = 0.03). The survival times can not be statistically compared due to the high level of survival in the chitosan group (see table 10).

TABLE 7 TABLE 8 TABLE 9 TABLE 10 This study of the ISR of the Army of the United States of North America (Pusateri et al., J. Trauma, 54, 177-182, (2003)) demonstrates, in an independent study, the significantly improved performance of the dressing. of chitosan with respect to the standard gauze of 10.16 cm x 10.16 cm. The ISR of the United States Army has only been able to demonstrate significantly improved performance with respect to the 10.16 cm x 10.16 cm gauze in the arrest of severe blood flow in the case of the claim dressing of this invention and in the case of a dressing. of thrombin and dry fibrin developed by the Red Cross. The Red Cross bandage is expensive, and it is also delicate and prone to rupture.

EXAMPLE 4 Irradiation of bandages Apposites for control of hemorrhage based on chitosan of 10.16 cm x 10.16 cm of high molecular weight are prepared with 3M 9781 porous foam backing from an Icelandic shrimp source (lot S01115-1 of Genis). These are prepared with 2% acetic acid and 2% chitosan solution using a commercial lyophilizer company to prepare a large sterile batch of chitosan bandages (Lot # OMLC 2SM114). The bandages are irradiated at 15 kGy under nitrogen. These are subsequently evaluated for uniaxial tensile strength, burst strength, blood absorption, water absorption, as well as for sterility. Porcine aortic perforations are performed on non-irradiated samples with gamma radiation in abdominal and thoracic lesions. Seven patches are used. On average, the blood loss after applying the patch is < 50 ml. All patches are adherent, wound sealants and hemostatic in their first application (1 x 0 ratings). All the animals survive. Bandages not irradiated and irradiated with gamma radiation (Lot # OMLC_2SM114) are evaluated with an in vitro burst pressure test developed at the Oregon Medical Laser Center in Portland Oregon. To perform a burst test, a circular test piece of the 25 mm diameter bandage is immersed in citrate treated whole blood for 10 seconds. The test piece is then placed in a centered manner, and held firmly with digital pressure, over a 4 mm diameter hole in the side of a 50 mm diameter PVC tube for 3 minutes. After this initial connection, the fluid pressure inside the tube is increased to 4.5 ± 0.5 kPa s-1, recording the pressure and time at 0.1 second intervals. The burst pressure is recorded as the maximum pressure recorded before the failure. An adhesive failure rating is assigned to evaluate the relative adhesiveness of the bandage to the test site. The rating system is separated into three different failure modes. A grade of 1 is assigned to a test piece that can be easily separated from the PVC surface without remaining chitosan adhered. A score of 2 is assigned when the test piece comes off easily and a certain amount of the chitosan remains attached to the test site. A score of 3 is assigned when the test piece can only be removed by cohesive separation of the total dressing from the base structure which remains firmly attached to the PVC surface. The average burst pressure of irradiated and non-irradiated chitosan dressings with gamma radiation (mean ± standard deviation, n = 6) on a PVC substrate using blood as the wetting medium is 122 ± 1.9 kPa and 86 ± 20 kPa, respectively. The results are analyzed statistically using a T test (p = 0.007). The average adhesive failure ratings of irradiated and non-irradiated chitosan alpha dressings with gamma radiation (mean ± standard deviation, n = 6) on a PVC substrate using blood as the wetting medium are both 3 + 0. Figure 10 shows an image of a high rating fault in which the cohesive failure occurs within the chitosan structure. The blood and water absorption properties of the dressings (Lot # OMLC_2SM114) are determined by immersing small test pieces (approximately 0.02 g) in blood or water for 3.0 seconds. The difference in mass is recorded before and after the dive. The average mass of adsorbed medium is determined in 3 seconds by 1 gram of dressing for irradiated and non-irradiated chitosan samples with gamma radiation (n = 4) using blood or water as the wetting medium (see figure 11). The results are statistically analyzed using one-way ANOVA with a Tukey-HSD test, p = 0.001. Gamma irradiation significantly reduces the excessive adsorption of water in the case of unirradiated material. Said excessive adsorption of water can cause the collapse of the dressing (such as a gel) with subsequent adhesive and structural failure. Test pieces are evaluated for tensile strength of the chitosan dressings (Lot # • OMLC_2SM114) using a Vitrodyne V1000 device from Chatillon Materials Testing equipped with a 5 kg load cell. Samples are cut as dog bone pieces (15 ± 1 mm x 6.5 + 0.5 mm x 5 ± 0.5 mm gauge x thickness x width) and clamped between two clamps.

The crosshead speed is 10 mm / s. Load and displacement are recorded at 0.1 second intervals. The tensile results of the complete dressings are shown in Table 11. There are no significant differences between the irradiated and non-irradiated samples with gamma radiation with respect to both loading and mechanical deformation. There is a small increase in the Young's modulus with irradiation at 15 kGy.

TABLE 11 * calculated for a bandage of 2.5 cm wide 52 apitositos of chitosana of 10.16 cm x 10.16 cm (Lot # 0MLC_2SM114) are prepared neatly. From these 10.16 cm x 10.16 cm dressings, 46 are packaged in a double pack envelope and shipped to IsoMedix facilities in Ontario, California for irradiation with gamma radiation at a certified dose of 14-15 kGy. With these samples, we send a set of 8 chitosan dressing bars doped with Staphylococcus aureus (ATCC 29213) (2.54 cm x 0.533 cm x 0.533 cm) that are cut from the 2SM114 # 1 dressing. Each bar is inoculated with 100 μl of MacFarlane inoculum. Staphylococcus aureus is extracted from a demonstrably active control culture. Also included is a control set of 4 bars without Staphylococcus. Control samples without gamma radiation treatment are kept in small sterile containers in thermally sealed envelopes at room temperature and in the dark (see table 12 for a summary of controls).

TABLE 12 The 46 irradiated dressing packs are opened under sterile conditions with sterile handling, a foam backing is attached with sterile ethylene oxide adhesive (3M 9781 tape), a small cut-off piece is removed approximately (3.048 cm x 0.508 cm x 0.061) cm) of each dressing and backing for evaluation of individual dressing sterilization and the dressings are repacked inside the original inner packing material by thermal sealing. 40 of these apposites are marked with batch number and apposition number and sent for evaluation. The cut and control pieces are supplied to the microbiology building at St Vincent Hospital for sterility evaluation. Cut pieces and control pieces are aseptically placed in labeled sample containers (1.524 cm x 12.7 cm) containing enriched thioglycolate growth medium and incubated under aerobic conditions at 35 ° C. Culture media are examined at 7, 14 and 21 days for growth indications. Samples are subcultured on Tryptic Soy Agar (TSA) medium with 5% sheep blood, incubated at 35 ° C and examined for growth after 48 hours. The individual cultures are analyzed by turbidity analysis and collection of subculture samples (swabbing). The absence of any growth was demonstrated in all crops and in all sub-crops at 7, 14 and 21 days, even those crops that were not irradiated and were planted with Staphylococcus aureus. Gram positive staining of particular cultures confirms these findings.

EXAMPLE 5 Preparation of sponge Table 13 lists the hydrophilic polymers purchased for analysis. Additional hydrophilic polymers include polylysine, chondroitin sulfate, starch and hyaluronan. Aqueous solutions (2.00% and 8.00% by weight) of ultra-filtered water (Ametek) and hydrophilic powder are prepared in clean 1 liter bottles (Nalgene). The non-woven chitosan mats (PolyMed, Inc.) are converted into non-woven chitin mats by exposure to acetic anhydride (Aldrich 99%) over 48 hours at room temperature. The residual acetic anhydride is washed from the mat using multiple washes of ultra-filtered water. Exposure of the acetylated mats to NaOH (0.5 M) for 6 hours at room temperature hydrolyses the acetyl esters in carbons 3 and 5 of glucopyranose without any hydrolysis of the acetylamide in the carbon of position 2 (confirmed by FTIR analysis). A polyester fiber (200 microns under load of 20 N) twisted (1 / cm) ultrafine (4 microns in diameter) of multiple filaments (> 50) is acquired (Multicraft Plastics, Portland, OR).

TABLE 13 Glacial acetic acid (Aldrich 99.99%) is added to the aqueous solutions of 2% chitosan and 8% to 2% and 4% by weight of water respectively. The dissolution of the hydrophilic polymer solutions is achieved by slow axial rotation of the bottles at room temperature for a period of up to 24 hours in a rotating bed stirrer. All 2% solutions easily pass solution, and the highest viscosities measured in a Brookfield LVT viscosimeter at 25 ° C and number 2 and number 3 needle are less than 2000 centipoise. The 8% solutions of chitosan, alginic acid and acrylic acid have very high viscosities to be measured by the Brookfield viscometer. The very high viscosity fluid solutions in these cases prevent the solutions from being poured. Instead, the solutions are squeezed, pulled and removed by bucket from their plastic bottles to load the molds. The latter fluids with very high viscosity can not be easily processed in a manufacturing environment. The sponges are formed by pouring / placing aqueous solutions in cavities of 10.8 cm x 10.8 cm x 2.0 cm, coated with Teflon ™ in aluminum molds up to 1.7 cm deep in the case of aqueous solutions at 2% or 0.45-0.70 cm depth in the case of 8% solutions. The solutions, initially room temperature, are frozen as plates by placing the aluminum molds in cooling shelves at temperatures between -25 ° C and -45 ° C for 3 hours in freezers Virtis (0.65 m2) or Hull (3.72 m2 or 16.63 m2). Sublimation of the water from the plates to produce hydrophilic polymeric sponges is achieved using a pressure lower than 200 mTorr, condenser at -80 ° C with shelf temperature that is slowly increased from -45 ° C to 18 ° C in a 48-hour period. to 60 hours. In the case of a sample of the 2% chitosan solutions, four strategies are analyzed to stop the unwanted crust formation (ice nucleation on the upper surface) in the 2% chitosan solutions during freezing. One method is to place a thin polymer film on the upper surface of the molds and in intimate wetting contact with the surface of the polymer solution before placing it on the cold shelf for freezing. After the solution is frozen as a plate (approximately 1-2 hours), the protective polymeric film is removed. The polyvinylidene chloride film (eg, Saran ™ wrap) is particularly useful, because its glass transition temperature is below -45 ° C. The thin film acts to prevent the dendritic ice formed on cold surfaces inside the freezer / lyophilizer from being deposited on the surface of the super-cooled hydrophilic polymer top solution and present nucleation for a frozen surface crust. The second strategy to avoid this crust layer is the use of a thin acrylic plate (eg 3 mm) high (using 250 mm x 6 mm x 5 mm spacer bars) placed immediately above the mold. This has advantages over the thin film method, because it is not necessary to interrupt the freezer / lyophilizer cycle to remove the thin protective polymeric film that is in contact. A third method, indicated in more detail in Example 7, uses the non-woven mat backing application of permeable, permanent chitin on the surface of cast molded solutions. A fourth strategy, indicated in greater detail in Example 11, is used to seal with heat, sacks lined with thin metal foil and filled with hydrophilic solution as the containment of solution during freezing. Upon completion of lyophilization (> 48 hours), the sponges are removed from the dryer, weighed and stored in foil lined bags Thermally sealed The sponges are 10 cm x 10 cm x 1.7 cm in the case of solutions poured at 1.7 cm depth and 10 cm x 10 cm x 0.43 cm in the case of sponges poured to a depth of 0.45-0.7 cm. Moisture analysis using an Arizona Instruments Vapor Pro moisture analyzer demonstrates% residual moisture between 1% and 4% of the sponge mass. The residual acetic acid in the chitosan sponges is determined using an automated titrant Mettler DL53 and 0.010 M NaOH and is between 27% and 22% of the mass of the sponge. The average sponge densities for the chitosan sponges of the 2% and 8% solutions are 0.031 + 002 g / cm3 and 0.103 ± 0.014 g / cm3, respectively. The average sponge densities for the other hydrophilic sponges are 0.0248 ± 0.0036 g / cm3 for sponges at 2% and 0.0727 ± 0.0023 g / cm3 for sponges at 8%. The average density difference of 29% between chitosan sponges and other hydrophilic sponges is mainly caused by acetic acid in chitosan sponges and a small fraction of volatile components not considered when weighing non-chitosan sponges. The 2% sponges from all the different hydrophilic test polymers are all well formed, flexible and similar in appearance and structure. All shrink about 8% across and across. The alginate and chitosan sponges have very good cohesive properties, resist tearing and cracking caused by handling. Dextran, carboxymethylcellulose and polyacrylic acid sponges are less cohesive, easily crack and tear with handling. The typical appearance of a 2% sponge frozen at a temperature close to -30 ° C is shown in figure 12. The edges have a smooth appearance and are decorated with a regular mosaic structural pattern. The upper side of the sponge has a slightly domed structure in the center. The only apparent feature is the formation of regular pustules 0.5 mm in diameter x 0.5 mm deep. The base surface (ie, the surface in contact with the base of the Teflon ™ mold has a surface texture and apparent regions of "large individual glass" separated by grain boundaries.) A cross section cut using single-bladed knives. edge (Figure 13) demonstrates the internal structure.The grain boundaries in the base surface can be observed as boundaries that demarcate regions of thin lamellae oriented in different directions and that probably originate from different heterogeneous nucleation events on the surface of the surface. The internal structure of the sponge can be described by a base layer of thin lamellae (each 2-5 micrometers thick) that extend up to and into the sponge and cover about 60% of the thickness of the sponge. Immediately above the base lamella is a thin interface (<; 10 microns) that separates the thin base layer from the upper thick layer. This thick layer originates from the strange dendritic ice that comes into contact with the upper surface solution when the temperature of the upper solution falls below 0 ° C. The lamellae in this layer are larger than 10 microns thick and are generally oriented vertical with respect to the upper surface. These vertical, thick lamellas resist compression in the normal plane with respect to the plane of the sponge. Chitosan sponges formed by protecting the upper surface against nucleation with dendritic ice do not have a superior crust structure. These sponges have improved mechanical performance in terms of resistance to cracking, and improved elasticity (flexibility) compared to sponges that are formed without top surface protection. All 2% sponge surfaces easily adsorb water or blood. All uncompressed sponges are highly susceptible to collapse as a gel if they come in contact with excess water or blood for brief periods of time (ie, 5 seconds or more). Sponges at 8% are considerably stiffer than sponges at 2%. The fine structure at the base of the sponge, which seems closed and smooth, can not easily be observed. These sponges do not adsorb blood and water as easily as sponges compressed to 2%. When cutting cross sections of these sponges, it can be seen that the internal structure is not different from that in the 2% sponges: the thick upper vertical structure is present at a depth close to the same relative depth as in the 2% sponge (ie, 30-40%), and the base layer consists of highly compact areas of lamellae oriented at an angle close to 30 ° from the normal and delimited by fine grain boundaries. Sponges from the 2% solution are typically compacted by heating plates of parallel plates coated with Teflon ™ at 80 ° C, and joining the plates to a constant separation distance (typically 0.55 cm) at a constant speed between 1200 mm / minute up to 5 mm / minute. The sponge density of a sponge of 1.70 cm thickness compacted to 0.45 cm is approximately 0.10 g / cm3. Sponges compacted at less than 80 ° C and / or at a compression speed greater than 20 mm / minute are susceptible to mechanical failure due to cracking in grain boundaries and brittle failure. It is found that this is the case in sponges of 2% chitosan, 1.7 cm thick compacted at a speed greater than 60 mm / minute. Of the 864 sponges, more than 260 sponges are discarded due to brittle collapse and failure. When the compression speed is set at 20 mm / minute, only 43 of the 864 sponges are discarded. When the compression speed is adjusted to 10 mm / minute, less than 9 sponges are discarded. The change in structure of the sponge when compacting at slow speeds (<12 mm / minute) is shown in figure 13. It can be seen that the thin base plates oriented at an angle between 20 ° and 40 ° with respect to the vertical they can be easily densified (75% compression) to a uniform base layer, while the vertical thick top layer only partially densifies (approximately 55% compression). At slow compression speeds, the grain boundary regions remain in intimate contact. At higher compression rates (> 20 mm / minute), the grain boundary regions are more likely to separate. Compressed sponges (observation with respect to hydrophilic sponges) are less easily wetted with water or blood and these they are more resistant to dissolution in both media. The sponges compressed to 2%, although they are well moisturized by the blood do not dissolve. The adhesive strength of wet compressed sponges is classified as PAA >; chitosan > CMC > alginic acid. A very important determinant of an effective sponge is the presence of ortho-normal microscopic size indentations (figure 14) on the surface of the lamellae. These indentations are projected from 3 to 10 microns from the surface of the lamellae as small "teeth". Ideally these should be distributed in a regular manner on at least one surface of the foil. These structures are more common under controlled conditions when the lamellae are formed in lamella growth orientations greater than 30 ° with respect to the vertical. These also appear to be controlled by a capacity to rapidly cool the frozen plate to a temperature below -45 ° C after the initial period of 30 to 60 minutes of freezing at -25 ° C. After compacting, the test chitosan sponges are baked in a constant temperature convection oven at 80 ° C for 30 minutes to temper the residual stresses and remove free acetic acid residues.

EXAMPLE 6 Preparation of 2% chitosan sponges A. Two samples of 2% chitosan sponges (N = 3): a sample is compacted from 1.7 cm to 0.55 cm at 20 mm / minute while the other is not compacted. Both samples are baked at 80 ° C for 30 minutes. Square test pieces (5 cm x 5 cm) are cut from each sponge. A test piece is moistened with porcine whole blood treated with citrate by immersion of 10 seconds in blood at room temperature. This is fixed in a centered manner on a perforation of 4 mm in diameter on a surface of 10 cm x 10 cm of transparent PVC of 12 mm thickness (which is made rough using sandpaper for water and dry of 400 grains) by means of Digital pressure (200-300 mm Hg) for 3 minutes. The pressure of whole swine blood at room temperature is increased in a reservoir below the perforation (almost 50 mm Hg / s). A pressure transducer is attached to the tank to measure the maximum pressure until it fails. The sponge test pieces (N = 3) that are compacted maintain pressure up to a pressure greater than 500 mm Hg. The failure in these sponges is due to the loss of adhesive bond to PVC. The sponge test pieces that have not been compacted (N = 3) fail at a pressure less than 500 mm Hg and the failure is due to collapse of the sponge and dissolution in the blood.

B. Chitosan sponges of 2% solution (N = 5) are compacted from 1.7 cm to 0.55 cm at 10 mm / minute. Bake at 80 ° C for 30 minutes; They are backed with PVC tape with foam and sterilized with gamma radiation (15 kGy). The test pieces (5 cm x 5 cm) are immersed in porcine whole blood at room temperature for 10 seconds. The test piece is then centered in a 4 mm diameter perforation on a flat PVC surface and held at a loading pressure (about 600 mm Hg) for 3 minutes. At the end of this period, the pressure of whole swine blood at room temperature below the perforation (about 50 mm Hg / s) is increased to 300 mm Hg for 3 minutes and then increased again at a similar speed until the attached test piece fails. The failure of the test piece occurs when the blood pressure is greater than 1800 mm of mercury. The failure can be due to cohesive rupture, dissolution of the upper crust layer or adhesive loss of the PVC bond.

C. A test piece of chitosan sponge (4 cm x 4 cm x 0.5 cm) prepared from an 8% solution is found to be effective in stopping bleeding in a 4 mm sharp porcine aortic perforation in diameter (mean arterial blood pressure of 70 mm Hg; haemostatic bandage test piece for more than 30 minutes). However, sponges from the 8% chitosan solution are inflexible and can not be easily adjusted to a wound. On the other hand, sponges of the same density, formed from 2% chitosan solutions but that are compacted from 1.37 cm to 0.45 cm, are not only effective in stopping bleeding in this aortic perforation lesion, but also They are easily flexible and become more flexible over time when placed against the bleeding wound.

D. Test pieces of 2.54 cm in diameter (N = 12) from slowly-compacted 2% solution chitosan bandages (1.70 cm to 0.45 mm) initially formed from crust-free sponges are attached (digital pressure for 3 days). minutes to bleeding initially with free flow, average blood pressure of 70 mm Hg) to perforated aortas (4 mm diameter) in 12 anesthetized pigs. All test pieces stop bleeding in the first application and are hemostatic over an interval of at least 30 minutes. In comparison, chitosan bandages formed from bandages with a crust layer (N> 100) take on average 0.5 to 1.5 re-applications of pressure to stop bleeding with respect to the same time interval.

E. Oval test pieces (3.8 cm x 3.2 cm) (N = 10) of 2% chitosan sponges are compacted at rapid speed (> 50 mm / minute) into porcine whole blood at room temperature for 10 seconds. The test pieces are then centered in a 4 mm diameter bore in a flat PVC surface and clamped with 50 mm Hg digital pressure for 3 minutes. At the end of this period, the whole porcine blood, at room temperature, under the perforation is pressurized (to almost 50 mm of Hg / s) up to 300 mm of Hg / s during 3 minutes and then it is increased again (approximately 50 mm Hg / s) until the test pieces fail. Failure is rated in terms of maximum pressure obtained, final adhesion to the test fixture, and cohesion of the bulk sponge after failure. These results are compared with the results of similar analysis of 20 test pieces of 2% chitosan sponges that are compacted slowly (compression rate <15 mm / minute). The ratings for final burst and adhesion are similar; however 60% of the compacted sponges quickly have the lowest possible cohesion ratings due to dissolution than coarse crust and gelling whereas all 20 compacted bandages have the highest cohesion ratings.

F. Two sets of 2% chitosan sponges are prepared. One set has substantial lamellar surface indentations, the other set has no indentations on the surfaces of the lamellae. Both sets of sponges are compacted at slow compaction speeds up to a density close to 0.10 g / cm3. The sponges are baked at 80 ° C for 30 minutes and backed with PVC foam film. In the experiments of porcine aortic perforation, the set of sponges with indented lamellae are effective to stop the severe arterial bleeding in all cases (N = 12). In sponges without indented lamellae (N = 6) none of the test pieces is effective in stopping bleeding.

EXAMPLE 7 Preparation of chitosan sponge with chitin mesh reinforcement A non-woven chitin mesh soaked in water is placed against absorbent cloths (Kimwipe ™) to reduce the amount of water in the non-woven chitin mesh. The mesh is cut as a square of 10 cm x 10 cm. This is then placed on the surface of a 2% chitosan solution poured into a cavity of an aluminum mold of 10.8 cm x 10.8 cm x 2 cm depth. It is observed that the mesh remains suspended on the surface of the chitosan and that a certain amount of chitosan adsorption occurs superficially in the mesh. The chitosan solution and the mesh are placed in the laboratory lyophilizer (Virtis). The solution is frozen, and the water is sublimated to reveal a sponge with a woven mesh firmly attached to its surface. The sponge with the chitin mesh dries at the same speed as a sponge without chitin mesh. A section of the sponge backed with chitin is cut in cross section to reveal the partial infiltration of the chitosan into the mesh at a depth of about 1.5 mm. However, the section also reveals that 1 mm of the upper part of the mesh surface is free of chitosan. The sponge with the mixed surface of chitin mesh is compacted at 20 mm / minute between parallel plate sinks heated to 80 ± 2 ° C from 1.8 cm to 0.45 cm in thickness. The cross section through the sponge after compacting shows that the interface between the chitin mesh and the chitosan sponge has not been damaged by the compaction and that both the mesh and the sponge are firmly fixed to each other. In addition, the presence of the chitin mesh stops the formation of the sponge crust (thick nucleation of ice from the upper surface downwards) that can affect the flexibility of the sponge and the resistance of the sponge to dissolution. The sponge is evaluated in a model of aortic perforation of 4 mm of acute porcine diameter. Bleeding from this lesion is not stopped by regular chitosan bandage pieces and the chitin-backed test piece is applied while maintaining digital pressure for 3 minutes. The surgeon who applies the 2.5 cm diameter test piece notices that the test piece is particularly flexible and that he can remove his finger without it adhering to the chitin backing. The test piece seals the site of the injury for a time longer than the required 30-minute test period of the protocol. This remains well adhered to the site of the injury and shows no signs of dissolution even when it does not have the protective waterproof backing normally applied with this bandage. further, it is observed that the bandage fits over the lesion because it is possible to observe a pulse through the flexion of the bandage.

EXAMPLE 8 Fiber impregnated with chitosan The 0.05 mm diameter polyester multi-filament submerged in 2% chitosan solution expands to approximately 2 mm in diameter. The fiber submerged in chitosan at room temperature rests gently on an aluminum tray coated with flat hydrophobic Teflon without removing any of the solution out of the expanded fiber. The tray is placed on the shelf of the Virtis lyophilizer at -25 ° C and allowed to freeze. The ice is removed from the fiber by freeze drying leaving an expanded fiber of 2 mm in diameter impregnated with chitosan sponge at 0.033 g / cm3. The application of a tensile force of about 10 N to the expanded fiber and a pressure of approximately 500 mm of normal Hg to the surface of the fiber through a die of non-adhesive pressing of nitrile rubber tapered compresses the diameter of the fiber from 2 mm to 0.7 mm. The fiber has adequate flexibility and is prepared to be woven like a gauze-type gauze. A portion of the fiber is baked at 80 ° C for 10 minutes. This is then immersed in blood for 10 seconds and held firmly against a clean PVC test surface for 3 minutes. This shows good adhesion.

EXAMPLE 9 Comparative flexion between compressed low density sponges and non-compacted high density sponge The densification method presented in the description reduces a highly flexible, low density interconnected sponge in volume by a controlled reduction in thickness, width and / or radius. Preferably, the flexibility of the hydrophilic polymers is not modified by plasticizers such as glutamic acid and glycerol, because this modification makes the sponges more susceptible to dissolution and collapse of the sponge under severe bleeding. This example shows that compression of low density sponges to higher density sponges results in sponges with a lower elastic modulus than if the sponge of the highest chemically identical density were formed without densification. In order to determine the elastic modulus (E), the deflections of the horizontal are determined in experiment with cantilever bar, individual. Rectangular bars are cut from compacted 2% sponges and 8% non-compacted sponges. The bars are 9 cm long and 2.5 cm wide. These are anchored so that only 6.7 cm of the bar extends from the edge of a flat horizontal surface. A weight of 20 g or 30 g is placed on the tip of the bar at 6.5 cm from the anchor point. The deflection of the 6.5 cm point of the normal bar from the horizontal is measured 3 seconds after loading. The elastic modulus (E) is determined from the equation E = P.L3 / (3y.I) In which I = W.h3 / 12 P = load (N); L = free length of the bar (m); "y" = deflection of the bar from the horizontal (m); w = bar width (m); H = height of the bar in the vertical plane (m); I = moment of inertia (m4).

The thickness of the bar is determined using a digital calibrator. After determining the deflection of the bar, the bar is cut into 2.54 cm x 2.54 cm pieces, weighed and density is determined. The results of the evaluation are shown in Table 2. It can be seen that the 8% samples are all more resistant to bending than the 2% samples. The average elastic modulus (MPa) for compacted 2% sponge are 6.43 ± 3.3, 1.75, 3.5 and 2.9 ± 0.4 for chitosan, polyacryl acid, carboxymethylcellulose, and alginic acid, respectively. The average elastic moduli (MPa) for 8% sponges are 10.6 ± 3.3, 12.4, 4.54 and 5.7 ± 2.1 for chitosan, polyacrylic acid, carboxymethylcellulose, and alginic acid, respectively. The ratio of average elastic moduli of compacted sponges to 2% with respect to 8% sponges is 0.61, 0.14, 0.77 and 0.51 for chitosan, polyacrylic acid, carboxymethylcellulose, and alginic acid, respectively.

TABLE 14 PAA polyacrylic acid, CMC = carboxymethylcellulose, AA = alginic acid EXAMPLE 10 Test pieces (5 cm x 5 cm) of mixed polyacrylic acid sponges, of compacted 2% solution (N = 2) are immersed in porcine whole blood at room temperature for 10 seconds. The test piece is then centered in a 4 mm diameter perforation on a flat PVC surface and held at a loading pressure (750 mm Hg) for 3 minutes. At the end of this period, the pressure of whole swine blood at room temperature below the perforation (about 50 mm Hg / s) is increased to 300 mm Hg for 3 minutes and then increased again at a similar speed until the attached test piece fails. The failure of the test piece occurs when the blood pressure is greater than 2300 mm Hg. Failure is due to cohesive breaking of the sponge.

EXAMPLE 11 A strategy to achieve excellent thermal contact with the freezing shelves, stop the course of scab formation during freezing and apply a controlled level of normal shear stress to the growing vertical lamellae is described. Fill sacks with thin metal foil, heat-sealed (15 cm x 23 cm) with 200 g of 2% chitosan solution. All air is removed from the bag before the final seal. The bags are placed in a laboratory Virtis lyophilizer between panels of parallel plates at -25 ° C to freeze for at least 180 minutes. The Virtis dryer has a "lid" installation that allows the upper shelf to be lowered over the lower shelf and therefore makes contact and firmly apply a load to the thin metal sheet sacks, filled with chitosan, placed between spacers in the lower shelf. The sacks are filled to such a level that when the upper shelf is lowered over the lower one, the upper shelf rests firmly on the upper surface of the sack filled with solution. The degree of pressure on the sack can be controlled by the free weight of the upper shelf and by the number of sacks resting between the two shelves. In this example, 1.7 cm spacer bars are used, only 2 sacks are placed between the shelves and the load on the sacks is approximately 10 kg. Before lyophilizing, the covered shelves are raised; the frozen plates are removed from their bags and placed on the cold shelves of the lyophilizer. The expansion inside the sacks during freezing is accommodated by partial internal tears of the thermal seal. The plates are subsequently lyophilized inside the sponges. The cross section through the sponge shows uniform lamella structures that grow from the upper and lower surfaces and are in the middle part of the sponges. The upper structure is the mirror image of the lower structure. All these lamellas are uniformly oriented at an angle between 20 ° and 30 ° with respect to the vertical and in the opposite direction from the center towards the edge of the sponge. The sponges demonstrate an absence of grain boundaries. The sponges are compacted from 1.7 cm thick to 0.55 cm. These have excellent mechanical properties in terms of tensile strength, flexibility and resistance to tearing or fracturing when bending severely. The sponges are baked, backed with PVC foam and irradiated with gamma radiation at 15 kGy. An individual oval test piece is applied to the perforation of an aorta in the acute pig model. This is effective to stop arterial bleeding through the 30-minute test period. The surgeon warns that the sample has excellent flexibility.

EXAMPLE 12 A simple positive textured surface is created on a 10 cm x 10 cm x 1.7 cm chitosan sponge. This It is achieved by using an aluminum card with a negative pattern of 10 cm x 10 cm x 0.25 cm. The pattern is carried out by running a wet and dry paper of 400 grains on the flat aluminum surface. This surface is coated with a non-permanent red dye, most of which is removed from the upper portion of the surface by rubbing with a dry cloth. A chitosan sponge that is compressed against this surface demonstrates the formation of a positive surface pattern because it is revealed by the red dye on the aluminum card. All references discussed above are incorporated in the present invention for reference in their entirety for all purposes. Although this invention has been presented and described in particular with reference to preferred embodiments thereof, those skilled in the art will understand that various changes in form and details may be made therein without departing from the scope and scope of the invention as defined by the appended claims.

Claims

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the content of the following is claimed as property: CLAIMS 1. - A compressed sponge for hemorrhage control comprising a hydrophilic polymer, characterized in that the compressed sponge has a compressed sponge density of about 0.6 to 0.15 g / cm3. 2. The compressed sponge according to claim 1, characterized in that the hydrophilic polymer is an alginate, chitosan, a hydrophilic polyamine, a derivative of chitosan, poly-lysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulosic polymer, a dextran, hyaluronan or a combination thereof. 3. The compressed sponge according to claim 2, characterized in that the starch is selected from the group consisting of amylase, amylopectin and a combination of amylopectin and amylase. 4. The compressed sponge according to claim 1, characterized in that the hydrophilic polymer is chitosan. 5. The compressed sponge according to claim 4, characterized in that the chitosan has a weight average molecular weight of at least about 100 kDa. 6. The compressed sponge according to claim 4, characterized in that the chitosan has a weight average molecular weight of at least about 150 kDa. 7. The compressed sponge according to claim 4, characterized in that the chitosan has a weight average molecular weight of at least about 300 kDa. 8. The compressed sponge according to claim 4, characterized in that the chitosan has a viscosity at 25 ° C in a solution of acetic acid (AA) at 1% which is approximately 100 centipoise up to 2000 centipoise. 9. The compressed sponge according to claim 4, characterized in that the chitosan has a viscosity at 25 ° C in a solution of acetic acid (AA) at 1% which is about 125 centipoise up to about 1000 centipoise. 10. The compressed sponge according to claim 4, characterized in that the chitosan has a viscosity at 25 ° C in a solution of acetic acid (AA) at 1% which is from 150 centipoise to approximately 500 centipoise. 11. The compressed sponge according to claim 1, characterized in that the compressed sponge also comprises an active ingredient. 12. The compressed sponge according to claim 11, characterized in that the active ingredient is selected from the group consisting of calcium, thrombin, factor Vlla, factor XIII, thromboxane A2, prostaglandin-2a, epidermal growth factor, factor of platelet-derived growth, Von illebrand factor, tumor necrosis factor (TNF), TNF-alpha, transforming growth factor (TGF), TGF-alpha, TGF-beta, insulin-like growth factor, growth factor fibroblast, keratinocyte growth factor, nerve growth factor, penicillin, ampicillin, methicillin, amoxicillin, clavamox, clavulanic acid, amoxicillin, aztreonam, imipenem, streptomycin, kanamycin, tobramycin, gentamicin, vancomycin, clindamycin, erythromycin, polymyxin, bacitracin , amphotericin, nystatin, rifampin, tetracycline, doxycycline, chloramphenicol and a combination thereof. 13. A sponge of compressed mixed material for hemorrhage control comprising a hydrophilic polymer sponge and a wettable polymer matrix or wettable polymer matrices within the sponge and / or on the surface of the sponge. 14. The sponge of compressed mixed material according to claim 13, characterized in that the hydrophilic polymer is selected from the group consisting of alginate, a hydrophilic polyamine, a chitosan derivative, polylysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulosic material, a dextran, hyaluronan and a combination thereof. 15. The sponge of compressed mixed material according to claim 14, characterized in that the starch is selected from the group consisting of amylase, amylopectin and a combination of both amylopectin and amylase. 16. The sponge of compressed mixed material according to claim 13, characterized in that the wettable polymer is selected from the group consisting of non-woven mats, woven mats, molded polymer mesh and low density sponges. 17. The sponge of compressed mixed material according to claim 16, characterized in that the wettable polymer matrix is selected from the group consisting of a chitin, an alginate, a neutralized chitosan, a re-acetylated chitosan, a poly acid (glycolic acid), a poly (lactic acid), a poly (e-caprolactone), a poly (β-hydroxybutyric acid), a poly (β-hydroxyvaleric acid), a polydioxanone, a poly (ethylene oxide), an acid poly (malic), a poly (tartronic acid), a polyphosphazene, a polyethylene, a polypropylene, a metallocene polymer, a polyurethane, a polyvinyl chloride polymer, a polyester, a polyamide and a combination thereof. 18. The sponge of compressed mixed material according to claim 13, characterized in that the hydrophilic polymer is chitosan. 19. The sponge of compressed mixed material according to claim 18, characterized in that the chitosan has a weight average molecular weight of at least about 100 kDa. 20. The sponge of compressed mixed material according to claim 18, characterized in that the chitosan has a weight average molecular weight of at least about 150 kDa. 21. The compressed mixed material sponge according to claim 18, characterized in that the chitosan has a weight average molecular weight of at least about 300 kDa. 22. The sponge of compressed mixed material according to claim 18, characterized in that the chitosan has a viscosity at 25 ° C in a solution of acetic acid (AA) at 1% which is 100 centipoise approximately up to 2000 centipoise approximately . 23. The sponge of compressed mixed material according to claim 18, characterized in that the chitosan has a viscosity at 25 ° C in a solution of acetic acid (AA) at 1% which is from 125 centipoise to approximately 1000 centipoise approximately . 24. The sponge of compressed mixed material according to claim 18, characterized in that the chitosan has a viscosity at 25 ° C in a solution of acetic acid (AA) at 1% which is from 150 centipoise to approximately 500 centipoise approximately . 25. The sponge of compressed mixed material according to claim 13, characterized in that the sponge comprises a textile fiber impregnated with a hydrophilic polymer. 26. The sponge of compressed mixed material according to claim 25, characterized in that the textile fiber is impregnated with a hydrophilic polymer. 27. The sponge of compressed mixed material according to claim 26, characterized in that the hydrophilic polymer is chitosan. 28.- The sponge of compressed mixed material according to claim 26, characterized in that the hydrophilic polymer is alginate, a hydrophilic polyamine, a derivative of chitosan, poly-lysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulosic polymer, a dextran, hyaluronan or a combination thereof. 29. The sponge of compressed mixed material according to claim 28, characterized in that the starch is selected from the group consisting of amylase, amylopectin and a combination of both amylopectin and amylase. 30. The sponge of compressed mixed material according to claim 13, characterized in that the wettable mesh is a non-woven mesh. 31. The sponge of compressed mixed material according to claim 13, characterized in that the sponge contains pores with pore diameters of about 15 microns to about 300 microns. 32. The sponge of compressed mixed material according to claim 13, characterized in that the sponge contains pores with pore diameters of about 30 microns to about 250 microns. 33. The sponge of compressed mixed material according to claim 13, characterized in that the sponge contains pores with pore diameters of approximately 100 microns to approximately 225 microns. 34. The sponge of compressed mixed material according to claim 13, characterized in that the sponge contains pores with pore diameters of approximately 125 microns to approximately 200 microns. 35.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge contains pores with pore diameters of approximately 150 microns to approximately 175 microns. 36.- The compressed mixed material sponge according to claim 13, characterized in that the sponge has a surface area available for contact with blood per sponge base surface of approximately 100 cm2 per cm2 to approximately 1000 cm2 per cm2 . 37.- The compressed mixed material sponge according to claim 13, characterized in that the sponge has a surface area available for contact with blood per sponge base surface of approximately 200 cm2 per cm2 to approximately 800 cm2 per each cm2. 38.- The compressed mixed material sponge according to claim 13, characterized in that the sponge has a surface area available for contact with blood per sponge base surface of approximately 300 cm2 per cm2 to approximately 500 cm2 per each cm2. 39.- The sponge of compressed mixed material according to claim 18, characterized in that the available mass of bio-material of chitosan per surface area of the wound is approximately 0.02 g / cm2 up to approximately 1.0 g / cm2. 40.- The sponge of compressed mixed material according to claim 18, characterized in that the available mass of bio-material of chitosan per surface area of the wound is approximately 0. 04 g / cm2 up to approximately 0.5 g / cm2. 41.- The sponge of compressed mixed material according to claim 18, characterized in that the available mass of bio-material of chitosan per surface area of the wound is approximately 0.06 g / cm2 up to approximately 1.0 g / cm2. 42.- The compressed mixed material sponge according to claim 13, characterized in that the compressed mixed material sponge also comprises a backup support layer. 43.- The compressed mixed material sponge according to claim 42, characterized in that the back support layer is a layer of polymeric material. 44.- The sponge of compressed mixed material according to claim 43, characterized in that the polymeric material is a non-biodegradable synthetic material or a biodegradable polymer normally present in nature. 45.- The sponge of compressed mixed material according to claim 44, characterized in that the synthetic biodegradable material is selected from the group consisting of poly (glycolic acid), poly (lactic acid), poly (e-caprolactone), poly (ß-hydroxybutyric acid), poly (β-hydroxyvaleric acid), polydioxanone, poly (ethylene oxide), poly (malic) acid, poly (tartronic acid), polyphosphazene, the copolymers of the monomers used to synthesize said polymers and combinations thereof. 46.- The sponge of compressed mixed material according to claim 43, characterized in that the polymer normally present in nature is selected from the group consisting of chitin, algin, a starch, dextran, collagen, albumin and a combination of the same. 47.- The compressed mixed material sponge according to claim 44, characterized in that the synthetic non-biodegradable material is selected from the group consisting of polyethylene, polypropylene, a metallocene polymer, a polyurethane, a polyvinyl chloride polymer , a polyester and a polyamide. 48. The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a degree of adhesion to the wound site of about 40 kPa to about 500 kPa. 49.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a degree of adhesion to the wound site of about 60 kPa to about 250 kPa. 50.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a degree of adhesion to the wound site of about 100 kPa to about 200 kPa. 51.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of mixed material can form an adhesive material in combination with the blood flowing from said wound in a blood-dressing interface. 52. The compressed mixed material sponge according to claim 51, characterized in that the adhesive material is a chitosan adhesive material. 53. The sponge of compressed mixed material according to claim 52, characterized in that the adhesive material based on chitosan preferably has a pH of no more than about 5.5 when the wound is sealed. 54.- The sponge of compressed mixed material according to claim 52, characterized in that the adhesive material based on chitosan preferably has a pH of no more than about 4.5 when the wound is sealed. 55.- The sponge of compressed mixed material according to claim 52, characterized in that the adhesive material based on chitosan preferably has a pH of no more than about 4.0 when the wound is sealed. 56.- The sponge of mixed material of compressed chitosan according to claim 52, characterized in that the adhesive material comprises an acid that is selected from the group consisting of acetic acid, formic acid, lactic acid, ascorbic acid, hydrochloric acid and citric acid. 57.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a thickness of not less than about 3.0 mm and not more than about 8 mm. 58.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a thickness of not less than about 3.5 mm and not more than about 7 mm. 59.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a thickness of not less than about 4.0 mm and not more than about 6 mm. 60.- The compressed mixed material sponge according to claim 13, characterized in that the compressed mixed material sponge has a final tensile stress of about 0.1 MPa to about 1.0 MPa. 61.- The sponge of compressed mixed material according to claim 13, characterized in that the compressed mixed material sponge has a final tensile stress of about 0.15 MPa to about 0.8 MPa. 62.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a final tensile stress of about 0.25 MPa to about 0.5 MPa. 63.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a final stretch of approximately 5%. 64.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a final stretch of approximately 10%. 65.- The sponge of compressed mixed material according to claim 13, characterized in that the sponge of compressed mixed material has a final stretch of approximately 15%. 66.- A process for preparing a compressed sponge according to claim 1 for hemorrhage control comprising: (a) preparing by freeze / lyophilization a low density sponge; and (b) compressing the low density sponge at a preferred rate of 10 mm per minute and at a preferred controlled temperature of 80 ° C whereby a compressed sponge with a density of about 0.1 to about 0.2 g / cm 3 is obtained. 67.- A method for preparing a compressed sponge for hemorrhage control according to claim 1 comprising: (a) compressing the subsequent low density sponge at a rate of approximately 10 mm per minute, at a controlled temperature of 80 ° C to obtain a compressed sponge with a density of approximately 0. 1 to about 0.2 g / cm 3, and in which said low density sponge has not been frozen or lyophilized before compacting. 68. - The method according to claim 67, characterized in that the low density sponge has a density of about 0.010 g / cm3 to about 0.035 g / cm3. 69.- The method according to claim 67, characterized in that the compressed sponge has a density of approximately 0.1 g / cm3 to approximately 0.15 g / cm3. A process for preparing a compressed mixed material sponge for hemorrhage control according to claim 13 comprising: a) de-gasifying a solution of bio-material from chitosan by heating the solution of bio-material from chitosan and applying an emptiness to it; b) freezing the bio-material solution of chitosan; c) removing the water from the interior of the frozen chitosan bio-material without damaging the structural integrity of the frozen chitosan bio-material in such a way that the water in the chitosan bio-material passes from a solid phase to a gaseous phase; d) compressing the bio-material of chitosan at a preferred rate of about 10 mm per minute thereby obtaining a compressed sponge with a density of about 0.1 to about 0.2 g / cm 3; and e) baking the compressed chitosan sponge at about 80 ° C for about 30 minutes. 71.- The method according to claim 70, characterized in that the temperature is gradually reduced over a predetermined time interval during the freezing of the bio-material of chitosan of step (b). 72.- The method according to claim 70, characterized in that the temperature of step (b) is a final freezing temperature not higher than about -25 ° C. 73.- The method according to claim 70, characterized in that the temperature of step (b) is a final freezing temperature not higher than about -35 ° C. 74.- The method according to claim 70, characterized in that the temperature of step (b) is a final freezing temperature not higher than about -45 ° C. 75.- The process according to claim 70, characterized in that the water removal is effected by lyophilization of the frozen chitosan bio-material. 76.- The method according to claim 70, which also comprises the step of adding gases that are selected from the group consisting of argon, nitrogen and helium back to the de-gasified chitosan solution before freezing. 77.- The method according to claim 70, characterized in that the compressed sponge is sterilized. 78.- The method according to claim 70, characterized in that the compressed sponge is sterilized by gamma irradiation. 79. A method for preventing severe bleeding in an individual comprising administering a compressed sponge according to claim 1 or a sponge of compressed mixed material according to claim 13 to said individual in need of the same. 80.- The method according to claim 79, characterized in that the individual is a mammal. 81. The method according to claim 79, characterized in that the mammal is human. 82. The method according to claim 79, characterized in that the individual suffers from severe bleeding in such a way that a total blood loss of 30-40% can result in a period of 20 to 30 minutes if the bleeding is not controlled . 83. The method according to claim 79, characterized in that the compressed sponge or sponge of compressed mixed material is applied with a pressure of approximately 60 to 80 kPa directly on the bleeding lesion and is kept in place for 3 to 5 minutes. before releasing, pack and bandage. 84. A bandage case for treating severe bleeding comprising compressed sponges according to claim 1 or a compressed sponge of mixed material according to claim 13, gauze rolls for packaging and an Ace bandage for bandaging a wound. 85.- A method for the mechanical mesh and mesh formation of the sponges according to claims 1 and 13 which comprises pressing the sides of the sponge that come into contact with the fabric against a microtextured surface. 86.- The method according to claim 85, characterized in that the microtextured surface is selected from the group consisting of surfaces prepared by chemical etching, surfaces prepared by surface ablation by ion beam, surfaces prepared by mechanical cutting and surfaces prepared by laser ablation. 87. A method for improving the mechanical traction of the sponges according to claims 1 and 13 comprising pressing the sides of the sponge that come into contact with the tissue against a microtextured surface. 88.- The method according to claim 87, characterized in that the microtextured surface is selected from the group consisting of surfaces prepared by chemical etching, and surfaces prepared by particle blasting techniques. 89.- A method for limiting or stopping the formation of thick crust on the surface of the sponges according to claims 1 and 13 which comprises covering the surface of the sponge with a polymeric film, a polymer plate, a plastic plate high or a breathable membrane film, impervious to moisture. 90.- A low density sponge, characterized in that the sponge is formed by compressing a sponge with a density of approximately less than 0.05 g / cm3 until said sponge reaches a density of approximately less than 0.08 g / cm3, and because the sponge it is formed by a procedure other than freezing or lyophilization. 91.- The low density sponge according to claim 90, characterized in that the sponge is formed using a method that is selected from the group consisting of a phase inversion procedure, sponges that are prepared by covalently joining components active to preformed dies, and foam forming techniques. 92.- The compressed sponge and the compressed mixed material sponge according to claims 1 and 13, characterized in that the sponges also comprise at least one additional hydrophilic polymer. 93.- The compressed sponge and the compressed mixed material sponge according to claim 92, characterized in that the hydrophilic polymer is selected from the group consisting of alginate, chitosan, a hydrophilic polyamine, a derivative of chitosan, poly-lysine , polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulose polymer, a dextran, hyaluronan and a combination thereof. 94. The compressed sponge according to claim 93, characterized in that the starch is selected from the group consisting of amylase, amylopectin, and a combination of amylopectin and amylase. 95.- The compressed sponge according to claim 92, characterized in that the hydrophilic polymer is chitosan.